US9994551B2 - Pyridazine derivatives as RORc modulators - Google Patents

Pyridazine derivatives as RORc modulators Download PDF

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US9994551B2
US9994551B2 US15/801,178 US201715801178A US9994551B2 US 9994551 B2 US9994551 B2 US 9994551B2 US 201715801178 A US201715801178 A US 201715801178A US 9994551 B2 US9994551 B2 US 9994551B2
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alkyl
dimethyl
difluorophenyl
halo
twice
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Benjamin Fauber
Monique Bodil Van Niel
Andrew Cridland
Christopher Hurley
Jonathan Killen
Stuart Ward
Paul Winship
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Genentech Inc
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Genentech Inc
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Definitions

  • the invention pertains to compounds that modulate the function of retinoid-receptor related orphan receptor RORc (ROR ⁇ ) and use of such compounds for treatment of autoimmune diseases
  • T helper 17 cells are interleukin (IL)-17 secreting CD4+ T cells involved in pathogenesis of autoimmune diseases such as rheumatoid arthritis, irritable bowel disease, psoriasis, psoriatic arthritis and spondyloarthridities.
  • the retinoic acid-related orphan receptor ⁇ (ROR ⁇ or RORc) is recognized as a transcription factor necessary for Th17 cell differentiation.
  • RORc is an orphan member of the nuclear hormone receptor subfamily that includes ROR ⁇ (RORa) and ROR ⁇ (RORb). RORc controls gene transcription by binding to DNA as a monomer. Selective modulation of RORc has been proposed as a route to discovery and development of Th17 cell-associated autoimmune diseases.
  • the invention provides compounds of formula I:
  • hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with R e ; or
  • heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with R e ;
  • heterocyclyl selected from: oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with R f ;
  • heterocyclyl-C 1-6 alkyl wherein the heterocycly is selected from oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with R f ;
  • hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; or tetrazolyl; each of which may be unsubstituted or substituted once or twice with R g ; or
  • heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; or tetrazolyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with R g ;
  • R a and R b together with the nitrogen atom to which they are attached may form a heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl or oxazepinyl, each may be unsubstituted or substituted once or twice with R f ;
  • the invention also provides and pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of preparing the compounds.
  • Alkyl means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one to six carbon atoms, i.e. C 1 -C 6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
  • Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
  • Alkynyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
  • alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
  • Alkoxyalkyl means a moiety of the formula R a —O—R b —, where R a is alkyl and R b is alkylene as defined herein.
  • exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and 1-(2-methoxyethyl)-3-methoxypropyl.
  • Alkoxyalkoxy means a group of the formula —O—R—R′ wherein R is alkylene and R′ is alkoxy as defined herein.
  • Alkylcarbonyl means a moiety of the formula —C(O)—R, wherein R is alkyl as defined herein.
  • Alkoxycarbonyl means a group of the formula —C(O)—R wherein R is alkoxy as defined herein.
  • Alkylcarbonylamino means a group of the formula —R—C(O)—NR′— wherein R is alkyl and R′ is hydrogen or alkyl.
  • Alkylcarbonylalkyl means a group of the formula —R—C(O)—R′ wherein R is alkylene and R′ is alkyl as defined herein.
  • Alkoxyalkylcarbonyl means a moiety of the formula —C(O)—R—R′, wherein R is alkylene and R′ is alkoxy as defined herein.
  • Alkoxycarbonylalkyl means a group of the formula —R—C(O)—R′ wherein R is alkylene and R′ is alkoxy as defined herein.
  • Alkoxycarbonylamino means a moiety of the formula R—C(O)—NR′—, wherein R is alkoxy and R′ is hydrogen or alkyl as defined herein.
  • Alkoxycarbonylaminoalkyl means a moiety of the formula R—C(O)—NR′—R′′—, wherein R is alkoxy, R′ is hydrogen or alkyl, and R′′ is alkylene as defined herein.
  • Alkoxycarbonylalkoxy means a group of the formula —O—R—C(O)—R′ wherein R is alkylene and R′ is alkoxy as defined herein.
  • Haldroxycarbonylalkoxy means a group of the formula —O—R—C(O)—OH wherein R is alkylene as defined herein.
  • Alkylaminocarbonylalkoxy means a group of the formula —O—R—C(O)—NHR′ wherein R is alkylene and R′ is alkyl as defined herein.
  • Dialkylaminocarbonylalkoxy means a group of the formula —O—R—C(O)—NR′R′′ wherein R is alkylene and R′ and R′′ are alkyl as defined herein.
  • Alkylaminoalkoxy means a group of the formula —O—R—NHR′ wherein R is alkylene and R′ is alkyl as defined herein.
  • Dialkylaminoalkoxy means a group of the formula —O—R—NR′R′ wherein R is alkylene and R′ and R′′ are alkyl as defined herein.
  • Alkylsulfonyl means a moiety of the formula —SO 2 —R, wherein R is alkyl as defined herein.
  • Alkylsulfonylalkyl means a moiety of the formula —R′—SO 2 —R′′ where where R′ is alkylene and R′′ is alkyl as defined herein.
  • Alkylsulfonylalkoxy means a group of the formula —O—R—SO 2 —R′ wherein R is alkylene and R′ is alkyl as defined herein.
  • Amino means a moiety of the formula —NRR′ wherein R and R′ each independently is hydrogen or alkyl as defined herein. “Amino thus includes “alkylamino (where one of R and R′ is alkyl and the other is hydrogen) and “dialkylamino (where R and R′ are both alkyl.
  • Aminocarbonyl means a group of the formula —C(O)—R wherein R is amino as defined herein.
  • N-hydroxy-aminocarbonyl means a group of the formula —C(O)—NR—OH wherein R is hydrogen or alkyl as defined herein.
  • N-alkoxy-aminocarbonyl means a group of the formula —C(O)—NR—R′ wherein R is hydrogen or alkyl and R′ is alkoxy as defined herein.
  • Aminocarbonylaminoalkyl means a group of the formula R 2 N—C(O)—NR′—R′′— wherein each R is independently hydrogen or alkyl, R′ is hydrogen or alkyl, and R′′ is alkylene as defined herein.
  • N-alkyl-aminocarbonyl means a group of the formula —C(O)—NH—R wherein R is alkyl as defined herein.
  • N-hydroxy-N-alkylaminocarbonyl means a group of the formula —C(O)—NRR′ wherein R is alkyl as defined herein and R′ is hydroxy.
  • N-alkoxy-N-alkylaminocarbonyl means a group of the formula —C(O)—NRR′ wherein R is alkyl and R′ is alkoxy as defined herein.
  • N,N-di-C 1-6 alkyl-aminocarbonyl means a group of the formula —C(O)—NRR′ wherein R and R′ are alkyl as defined herein.
  • Aminosulfonyl means a group of the formula —SO 2 —NH 2 .
  • N-alkylaminosulfonyl means a group of the formula —SO 2 —NHR wherein R is alkyl as defined herein.
  • N,N-dialkylaminosulfonyl means a group of the formula —SO 2 —NRR′ wherein R and R′ are alkyl as defined herein.
  • Alkylsulfonylamino means a group of the formula —NR′—SO 2 —R wherein R id alkyl and R′ is hydrogen or alkyl as defined herein.
  • N-(alkylsulfonyl)-aminoalkyl means a group of the formula —R—NH—SO 2 —R′ wherein R is alkylene and R′ is alkyl as defined herein.
  • N-(Alkylsulfonyl)aminocarbonyl means a group of the formula —C(O)—NH—SO 2 —R wherein wherein R is alkyl as defined herein.
  • N-(Alkylsulfonyl)-N-alkylaminocarbonyl means a group of the formula —C(O)—NR—SO 2 —R′ wherein R and R′ are alkyl as defined herein.
  • N-Alkoxyalkyl-aminocarbonyl means a group of the formula —C(O)—NR—R′—OR′′ wherein R is hydrogen or alkyl, R′ is alkylene, and R′′ is alkyl as defined herein.
  • N-Hydroxyalkyl-aminocarbonyl means a group of the formula —C(O)—NR—R′—OH′′ wherein R is hydrogen or alkyl and R′ is alkylene as defined herein.
  • Alkoxyamino means a moiety of the formula —NR—OR′ wherein R is hydrogen or alkyl and R′ is alkyl as defined herein.
  • Alkylsulfanyl means a moiety of the formula —SR wherein R is alkyl as defined herein.
  • Aminoalkyl means a group —R—R′ wherein R′ is amino and R is alkylene as defined herein.
  • Aminoalkyl includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of “aminoalkyl” may be substituted once or twice with alkyl to provide “alkylaminoalkyl” and “dialkylaminoalkyl” respectively.
  • Alkylaminoalkyl includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like.
  • Dialkylaminoalkyl includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.
  • Aminoalkoxy means a group —OR—R′ wherein R′ is amino and R is alkylene as defined herein.
  • Alkylsulfonylamido means a moiety of the formula —NR′SO 2 —R wherein R is alkyl and R′ is hydrogen or alkyl.
  • Aminocarbonyloxyalkyl or “carbamylalkyl” means a group of the formula —R—O—C(O)—NR′R′′ wherein R is alkylene and R′, R′′ each independently is hydrogen or alkyl as defined herein.
  • Alkynylalkoxy means a group of the formula —O—R—R′ wherein R is alkylene and R′ is alkynyl as defined herein.
  • Aryl means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring.
  • the aryl group can be optionally substituted as defined herein.
  • aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxy
  • Arylsulfonyl means a group of the formula —SO 2 —R wherein R is aryl as defined herein.
  • Aryloxy means a group of the formula —O—R wherein R is aryl as defined herein.
  • Alkyloxy means a group of the formula —O—R—R′′ wherein R is alkylene and R′ is aryl as defined herein.
  • Carboxy or “hydroxycarbonyl”, which may be used interchangeably, means a group of the formula —C(O)—OH.
  • Cyanoalkyl means a moiety of the formula —R′—R′′, where R′ is alkylene as defined herein and R′′ is cyano or nitrile.
  • Cycloalkyl means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Particular cycloalkyl are unsubstituted or substituted with alkyl. Cycloalkyl can optionally be substituted as defined herein. Unless defined otherwise, cycloalkyl may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino.
  • cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.
  • Cycloalkenyl means a cycloalkyl as defined herein that includes at least one double bond or unsaturation.
  • Exemplary cycloalkenyl include cyclohexenyl, cyclopentenyl, cyclobutenyl and the like.
  • Cycloalkylalkyl means a moiety of the formula —R′—R′′, where R′ is alkylene and R′′ is cycloalkyl as defined herein.
  • Cycloalkylalkoxy means a group of the formula —O—R—R′ wherein R is alkylene and R′ is cycloalkyl as defined herein.
  • Cycloalkylcarbonyl means a moiety of the formula —C(O)—R, wherein R is cycloalkyl as defined herein.
  • C 3-6 cycloalkyl-C 1-6 alkyl-carbonyl means a moiety of the formula —C(O)—R, wherein R is cycloalkylalkyl as defined herein.
  • Cyanoalkylcarbonyl means a moiety of the formula —C(O)—R—R′, wherein R is alkylene as defined herein and R′ is cyano or nitrile.
  • N-Cyano-aminocarbonyl means a moiety of the formula —C(O)—NHR, wherein R is cyano or nitrile.
  • N-Cyano-N-alkyl-aminocarbonyl means a moiety of the formula —C(O)—NRR′—R, wherein R′ is alkyl as defined herein and R is cyano or nitrile.
  • Cycloalkylsulfonyl means a group of the formula —SO 2 —R wherein R is cycloalkyl as defined herein.
  • Cycloalkylalkylsulfonyl means a group of the formula —SO 2 —R wherein R is cycloalkylalkyl as defined herein.
  • Forml means a moiety of the formula —C(O)—H.
  • Heteroaryl means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring.
  • the heteroaryl ring may be optionally substituted as defined herein.
  • heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl
  • Heteroarylalkyl or “heteroaralkyl” means a group of the formula —R—R′ wherein R is alkylene and R′ is heteroaryl as defined herein.
  • Heteroarylsulfonyl means a group of the formula —SO 2 —R wherein R is heteroaryl as defined herein.
  • Heteroaryloxy means a group of the formula —O—R wherein R is heteroaryl as defined herein.
  • Heteroarylcarbonyl means a group of the formula —C(O)—R wherein R is heteroaryl as defined herein.
  • Heteroaralkyloxy means a group of the formula —O—R—R′′ wherein R is alkylene and R′ is heteroaryl as defined herein.
  • halo refers to a substituent fluoro, chloro, bromo, or iodo.
  • Haloalkyl means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen.
  • exemplary haloalkyls include —CH 2 Cl, —CH 2 CF 3 , —CH 2 CCl 3 , perfluoroalkyl (e.g., —CF 3 ), and the like.
  • Haloalkoxy means a moiety of the formula —OR, wherein R is a haloalkyl moiety as defined herein.
  • An exemplary haloalkoxy is difluoromethoxy.
  • Heterocycloamino means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.
  • Heterocyclyl means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur).
  • the heterocyclyl ring may be optionally substituted as defined herein.
  • Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl and the like.
  • Such heterocyclyl may be optionally substituted as defined herein.
  • Heterocyclylalkyl means a moiety of the formula —R—R′ wherein R is alkylene and R′ is heterocyclyl as defined herein.
  • Heterocyclyloxy means a moiety of the formula —OR wherein R is heterocyclyl as defined herein.
  • Heterocyclylalkoxy means a moiety of the formula —OR—R′ wherein R is alkylene and R′ is heterocyclyl as defined herein.
  • Haldroxyalkoxy means a moiety of the formula —OR wherein R is hydroxyalkyl as defined herein.
  • Haldroxyalkylamino means a moiety of the formula —NR—R′ wherein R is hydrogen or alkyl and R′ is hydroxyalkyl as defined herein.
  • Haldroxyalkylaminoalkyl means a moiety of the formula —R—NR′—R′′ wherein R is alkylene, R′ is hydrogen or alkyl, and R′′ is hydroxyalkyl as defined herein.
  • Haldroxycarbonylalkyl or “carboxyalkyl” means a group of the formula —R—(CO)—OH where R is alkylene as defined herein.
  • Haldroxycarbonylalkoxy means a group of the formula —O—R—C(O)—OH wherein R is alkylene as defined herein.
  • Haldroxyalkylcarbonyl means a moiety of the formula —C(O)—R—R′, wherein R is alkylene as defined herein and R′ is hydroxy.
  • Haldroxyalkyloxycarbonylalkyl or “hydroxyalkoxycarbonylalkyl” means a group of the formula —R—C(O)—O—R—OH wherein each R is alkylene and may be the same or different.
  • “Hydroxyalkyl” means an alkyl moiety as defined herein, substituted with one or more, for example, one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group.
  • Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl
  • Hydrocycloalkyl means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.
  • Oxo means a group of the formula ⁇ O (i.e., an oxygen with a double bond).
  • a 1-oxo-ethyl group is an acetyl group.
  • Alkoxy hydroxyalkyl and “hydroxy alkoxyalkyl”, which may be used interchangeably, means an alkyl as defined herein that is substituted at least once with hydroxy and at least once with alkoxy.
  • Alkoxy hydroxyalkyl and “hydroxy alkoxyalkyl” thus encompass, for example, 2-hydroxy-3-methoxy-propan-1-yl and the like.
  • Rea or “ureido” means a group of the formula —NR′—C(O)—NR′′R′′′ wherein R′, R′′ and R′′′ each independently is hydrogen or alkyl.
  • “Carbamate” means a group of the formula —O—C(O)—NR′R′′ wherein R′ and R′′ each independently is hydrogen or alkyl.
  • Carboxy means a group of the formula —O—C(O)—OH.
  • “Sulfonamido” means a group of the formula —SO 2 —NR′R′′ wherein R′, R′′ and R′′′ each independently is hydrogen or alkyl.
  • Optionally substituted when used in association with an “aryl”, phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl” moiety means that such moiety may be unsubstituted (i.e., all open valencies are occupied by a hydrogen atom) or substituted with specific groups as related herein.
  • leaving group means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions.
  • Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
  • Module means a molecule that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.
  • Disease and Disease state means any disease, condition, symptom, disorder or indication.
  • “Inert organic solvent” or “inert solvent” means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like.
  • the solvents used in the reactions of the present invention are inert solvents.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound.
  • Protecting group means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen and/or oxygen atoms present in the reactants.
  • the terms “amino-protecting group” and “nitrogen protecting group” are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures.
  • Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like.
  • Bn benzyloxycarbonyl
  • CBZ benzyloxycarbonyl
  • p-methoxybenzyloxycarbonyl p-nitrobenzyloxycarbonyl
  • tert-butoxycarbonyl BOC
  • Solidvates means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrate.
  • Arthritis means a disease or condition that causes damage to joints of the body and pain associated with such joint damage. Arthritis includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions.
  • Respiratory disorder refers to, without limitation, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.
  • COPD chronic obstructive pulmonary disease
  • Subject means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term “subject” does not denote a particular age or sex.
  • “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state.
  • the “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
  • Treating” or “treatment” of a disease state includes, inter alia, inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, and/or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
  • treating when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
  • a structure shown herein may exist in multiple tautomeric forms, all such tautomers are encompassed by the structure.
  • the atoms represented in the structures herein are intended to encompass all naturally occurring isotopes of such atoms.
  • the hydrogen atoms represented herein are meant to include deuterium and tritium
  • the carbon atoms are meant to include C 13 and C 14 isotopes.
  • One or more carbon atom(s) of a compound of the invention may be replaced by a silicon atom(s), and it is contemplated that one or more oxygen atom(s) of a compound of the invention may be replaced by a sulfur or selenium atom(s).
  • the invention provides compounds of formula I:
  • hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with R e ; or
  • heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with R e ;
  • heterocyclyl selected from: oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with R f ;
  • heterocyclyl-C 1-6 alkyl wherein the heterocycly is selected from oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with R f ;
  • hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; or tetrazolyl; each of which may be unsubstituted or substituted once or twice with R g ; or
  • heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; or tetrazolyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with R g ;
  • R a and R b together with the nitrogen atom to which they are attached may form a heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl or oxazepinyl, each may be unsubstituted or substituted once or twice with R f ;
  • R 1 is fluoro
  • R 2 is hydrogen
  • R 2 is halo
  • R 2 is fluoro
  • R 3 is hydrogen
  • R 3 is halo
  • R 3 is C 1-6 alkyl.
  • R 4 is:
  • hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with R e ; or
  • heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with R e .
  • R 4 is:
  • hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with R e ; or
  • heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with R e .
  • R 4 is:
  • hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with R e ; or
  • heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with R e .
  • R 4 is:
  • hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with R e ; or
  • heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with R e .
  • R 4 is C 1-6 alkyl.
  • R 4 is halo-C 1-6 alkyl.
  • R 4 is hydroxy-C 1-6 alkyl.
  • R 4 is halo-C 1-6 alkylsulfonyl.
  • R 4 is aminocarbonyl-C 1-6 alkyl.
  • R 4 is C 1-6 alkylcarbonylamino.
  • R 4 is hydroxycarbonyl-C 1-6 alkyl
  • R 4 is C 1-6 alkoxycarbonyl-C 1-6 alkyl
  • R 4 is —C 1-6 alkylene-C(O)—NR a R b wherein the C 1-6 alkylene- may be substituted once or twice with R c .
  • R 4 is C 3-6 cycloalkyl which may be unsubstituted or substituted once or twice with R d .
  • R 4 is hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with R e .
  • R 4 is heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with R e .
  • R a is hydrogen
  • R a is C 1-6 alkyl.
  • R b is hydrogen
  • R b is C 1-6 alkyl.
  • R b is halo-C 1-6 alkyl.
  • R b is hydroxy-C 1-6 alkyl.
  • R b is C 1-6 alkoxy-C 1-6 alkyl.
  • R b is C 1-6 alkylsulfonyl-C 1-6 alkyl.
  • R b is C 3-6 cycloalkyl.
  • R b is C 3-6 cycloalkyl-C 1-6 alkyl.
  • R b is aminocarbonyl-C 1-6 alkyl.
  • R b is heterocyclyl selected from: oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with R f .
  • R b is heterocyclyl-C 1-6 alkyl wherein the heterocycly is selected from oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with R f .
  • R b is hetereoaryl selected from oxazolyl. isoxazolyl. oxadiazolyl. triazolyl. pyrrolyl. pyrazolyl. imidazolyl. or tetrazolyl. each of which may be unsubstituted or substituted once or twice with R g .
  • R b is heteroaryl-C 1-6 alkyl wherein the heteroaryl is selected from oxazolyl. isoxazolyl. oxadiazolyl. triazolyl. pyrrolyl. pyrazolyl. imidazolyl. or tetrazolyl. wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with R g .
  • R a and R b together with the nitrogen atom to which they are attached may form a heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl or oxazepinyl, each may be unsubstituted or substituted once or twice with R f .
  • R c is halo
  • R c is hydroxyl
  • R c is C 3-6 cycloalkyl.
  • R d is C 1-6 alkyl.
  • R d is halo
  • R d is hydroxyl
  • R d is oxo
  • R e is C 1-6 alkyl.
  • R e is halo
  • R e is hydroxyl
  • R e is oxo
  • R e is halo-C 1-6 alkyl.
  • R e is hydroxy-C 1-6 alkyl.
  • R e is C 1-6 alkoxy-C 1-6 alkyl.
  • R e is C 1-6 alkylsulfonyl-C 1-6 alkyl.
  • R e is C 3-6 cycloalkyl.
  • R e is C 3-6 cycloalkyl-C 1-6 alkyl.
  • R e is aminocarbonyl-C 1-6 alkyl.
  • R e is —C(O)NHR h .
  • R f is C 1-6 alkyl.
  • R f is halo
  • R f is hydroxyl
  • R f is cyano
  • R f is oxo
  • R f is C 1-6 alkylsulfonyl.
  • R f is halo-C 1-6 alkyl.
  • R f is hydroxy-C 1-6 alkyl.
  • R f is C 1-6 alkoxy-C 1-6 alkyl.
  • R f is C 1-6 alkylsulfonyl-C 1-6 alkyl.
  • R g is C 1-6 alkyl.
  • R g is hydroxyl
  • R g is hydroxy-C 1-6 alkyl.
  • R g is oxo
  • R h is C 1-6 alkyl.
  • R h is hydroxy-C 1-6 alkyl.
  • R h is halo-C 1-6 alkyl.
  • the compounds of the invention may be of formula Ia or Ib
  • R 1 , R 2 and R 4 are as defined herein.
  • the compounds of the invention are of formula Ia.
  • the compounds of the invention are of formula Ib.
  • the compounds of the invention are of formula II
  • heteroaryl selected from: pyridinyl; pyrimidinyl; pyridazinyl; pyrazinyl; oxadiazolyl; oxazoyl; oxazolidinyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with R i ;
  • heteroarylcarbonyl wherein the heteroaryl portion is selected from: pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; oxadiazolyl; oxazoyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with R i ;
  • heteroaryl-C 1-6 alkyl wherein the heteroaryl portion is selected from: pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; oxadiazolyl; oxazoyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with R′;
  • heterocyclyl selected from oxetanyl and azetedinyl which may be unsubstituted or substituted once or twice with R i ; or
  • heterocyclyl-C 1-6 alkyl wherein the heterocyclyl portion is selected from oxetanyl and azetedinyl and may be unsubstituted or substituted once or twice with R i .
  • m is: 0.
  • m is: 1.
  • n 0.
  • n 1
  • p is: 0.
  • p is: 1.
  • p is: 2.
  • p is: 0 or 1.
  • q is: 0.
  • q is: 1.
  • X is C.
  • X is O.
  • X is N.
  • Y is C.
  • Y is O.
  • Y is N.
  • R 1 is fluoro
  • R 2 is hydrogen
  • R 2 is halo
  • R 2 is fluoro
  • R 3 is hydrogen
  • R 3 is halo
  • R 3 is C 1-6 alkyl.
  • R 5 is C 1-6 alkyl
  • R 5 is oxo
  • R 6 is C 1-6 alkyl.
  • R 6 is halo-C 1-6 alkyl.
  • R 6 is hydroxy-C 1-6 alkyl.
  • R 6 is benzyl
  • R 6 is C 1-6 alkoxycarbonyl.
  • R 6 is C 1-6 alkylcarbonyl.
  • R 6 is C 1-6 alkylsulfonyl.
  • R 6 is aminocarbonyl
  • R 6 is hydroxy-C 1-6 alkylcarbonyl.
  • R 6 is heteroaryl selected from: pyridinyl; pyrimidinyl; pyrazinyl; oxadiazolyl; oxazoyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with R i .
  • R 6 is heteroarylcarbonyl wherein the heteroaryl portion is selected from: pyridinyl; pyrimidinyl; pyrazinyl; oxadiazolyl; oxazoyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with R i .
  • R 6 is heteroaryl-C 1-6 alkyl wherein the heteroaryl portion is selected from: pyridinyl; pyrimidinyl; pyrazinyl; oxadiazolyl; oxazoyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with R i .
  • R i is C 1-6 alkyl.
  • R i is halo-C 1-6 alkyl.
  • R i is hydroxy-C 1-6 alkyl.
  • R i is oxo
  • the compounds of the invention may be of formula IIa or IIb
  • the compounds of the invention are of formula IIa.
  • the compounds of the invention are of formula IIb.
  • the compounds of the invention are of formula III
  • the compounds of the invention are of formula IIIa, IIb, IIIc or IIId
  • the compounds of the invention are of formula IIIa.
  • the compounds of the invention are of formula IIIb.
  • the compounds of the invention are of formula IIIc.
  • the compounds of the invention are of formula IIId.
  • the compounds of the invention are of formula IV
  • the compounds of the invention are of formula IIIa, IIb, IIIc or IIId
  • the compounds of the invention are of formula IVa.
  • the compounds of the invention are of formula IVb.
  • the compounds of the invention are of formula IVc.
  • the compounds of the invention are of formula IVd.
  • the compounds of the invention are of formula V
  • the compounds of the invention are of formula IIIa, IIb, IIIc or IIId
  • the compounds of the invention are of formula Va.
  • the compounds of the invention are of formula Vb.
  • the compounds of the invention are of formula Vc.
  • the compounds of the invention are of formula Vd.
  • the invention also provides a method for treating a disease or condition mediated by or otherwise associated with the RORc receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.
  • the disease may be arthritis such as rheumatoid arthritis or osteoarthritis.
  • the disease may be asthma or COPD.
  • the disease may be psoriasis.
  • the disease may be muscular distrophy.
  • the starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis ; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds , Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions , Wiley & Sons: New York, 1991, Volumes 1-40.
  • the following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.
  • the starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
  • the reactions described herein may be conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about ⁇ 78° C. to about 150° C., for example, from about 0° C. to about 125° C., or conveniently at about room (or ambient) temperature, e.g., about 20° C.
  • Scheme A illustrates one synthetic procedure usable to prepare specific compounds of formula I, wherein X is halo or other leaving group and R 1 , R 2 , R 4 and R 5 are as defined herein.
  • step 1 of Scheme A fenchone compound a is reacted with trifluoromethanesulfonyl anhydride to yield an unsaturated trifluoromethanesulfonyl ester compound b.
  • step 2 compound b undergoes a first oxidation to form a camphor trifluoromethanesulfonyl ester compound c.
  • the oxidation of step 2 may be carried out using ozonation.
  • a second oxidation is made in step 3, using selenium dioxide, to provide a dioxo trifluoromethanesulfonyl ester compound d.
  • step 4 compound d undergoes reaction with aryl ketophosphonate ester e to give compound f.
  • step 5 compound f is reacted with hydrazine to to give cinnoline trifluoromethanesulfonyl ester compound g.
  • Compound g undergoes hydrolysis in step 6 to yield the corresponding hydroxy-cinnoline compound h.
  • An O-alkylation is then carried out in step 7 by reaction with alkylating agent i to give cinnoline ether compound j, which is a compound of formula I in accordance with the invention.
  • the invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
  • the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, for example 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
  • One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
  • Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • a particular manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • a compound or compounds of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
  • the pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
  • Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
  • the compounds of the invention may be formulated in a wide variety of oral administration dosage forms.
  • the pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component.
  • the pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
  • the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets may contain from about one (1) to about seventy (70) percent of the active compound.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term “preparation” is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
  • liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
  • Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents.
  • Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the compounds of the invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • the compounds of the invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • the compounds of the invention may be formulated for administration as suppositories.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
  • the compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the subject compounds may be formulated for nasal administration.
  • the solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray.
  • the formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
  • the compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
  • the compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by a metered valve.
  • the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatine or blister packs from which the powder may be administered by means of an inhaler.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial.
  • Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support.
  • the compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylazacycloheptan-2-one).
  • Sustained release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection.
  • the subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
  • the pharmaceutical preparations may be in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the compounds of the invention are useful for treatment of immune disorders generally.
  • the compounds may be used for treatment of arthritis, including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions.
  • the compounds may be used for treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • the compounds may be used for treatment of gastrointestinal disorder (“GI disorder”) such as Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension, and the like.
  • GI disorder such as Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension, and the like.
  • the compounds may be used for treatment of pain conditions such as inflammatory pain; arthritic pain, surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve injury; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.
  • pain conditions such as inflammatory pain; arthritic pain, surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve injury; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.
  • the compounds may be used for treatment of muscular sclerosis, Sjogren's disease, lupus, and pulmonary fibrosis.
  • the compounds may be used for treatment of cancer and inhibition or tumor growth, including prostate cancer and castrate-resistant prostate cancer.
  • LCMS High Pressure Liquid Chromatography-Mass Spectrometry
  • Method A Compounds were analyzed using the following conditions: Experiments were performed on a Waters ZMD single quadrupole mass spectrometer linked to a Hewlett-Packard HP1100 LC system with UV diode array detector and 100 position autosampler.
  • the spectrometer has an electrospray source operating in positive and negative ion mode. This system uses a Phenomenex Luna 3 ⁇ m C18(2) 30 ⁇ 4.6 mm column at ambient temperature and a 2.0 mL/minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. This was maintained for 1 minute before returning to 95% solvent A and 5% solvent B over the next 0.5 minute. Total run time was 6 minutes.
  • Method B Compounds were analysed using the following conditions: Experiments were performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector.
  • the spectrometer has an electrospray source operating in positive and negative ion mode.
  • This system uses an Acquity BEH C18 1.7 ⁇ m 100 ⁇ 2.1 mm column, maintained at 40° C. or an Acquity BEH Shield RP18 1.7 ⁇ m 100 ⁇ 2.1 mm column, maintained at 40° C. and a 0.4 mL/minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.4 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 5.6 minutes. This was maintained for 0.8 minute before returning to 95% solvent A and 5% solvent B over the next 1.2 minutes. Total run time was 8 minutes.
  • Microwave reactions were carried out using a Biotage® Initiator® in vials appropriate to the scale of the reaction and at the temperature and time described in the experimental details.
  • Reverse Phase High Pressure Liquid Chromatography was used to purify compounds where indicated. Separation using gradient elution on a Phenomenex Gemini C18 column (250 ⁇ 21.2 mm, 5 ⁇ m) as stationary phase and using mobile phase indicated, operating at a 18 mL/min flow rate using a Gilson UV/Vis-155 dual channel detector and Gilson GX-271 automated liquid handler.
  • Mass-directed auto-purification was used to purify compounds where indicated.
  • An Agilent 1260 infinity purifications system with Agilent 6100 series single Quadrupole LC/MS and XSEELECT CSH Prep C18 5 ⁇ m OBD, 30 ⁇ 150 mm column at RT was used.
  • the mobile phases were 0.1% aqueous formic acid and 0.1% formic acid in acetonitrile, flowing at 60 ml/min, with a 10%-95% gradient, over 22 min, with a specific focused gradient.
  • Phase separator cartridges are supplied by Biotage® as Isolute® phase separator cartridges.
  • Step 2 Methyl (1R)-3-[2-(2,6-difluorophenyl)-2-oxoethylidene]-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate and (1R)-methyl 3-(2-(2,6-difluorophenyl)-1-hydroxy-2-oxoethyl)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate
  • Step 3 Methyl (1R)-5-(2,6-fluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene-1-carboxylate
  • Step 4 (1R)-5-(2,6-Fluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene-1-carboxylic Acid
  • Step 2 1-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)ethan-1-one
  • Step 4 Trifluoro-methanesulfonic Acid (1R,4R)-3-[2-(2,6-difluoro-phenyl)-2-oxo-eth-(Z)-ylidene]-7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-yl ester and trifluoro-methanesulfonic Acid (1R,4R)-3-[2-(2,6-difluoro-phenyl)-2-oxo-eth-(E)-ylidene]-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl Ester
  • Step 5 Trifluoro-methanesulfonic Acid (1R,8S)-5-(2,6-difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-trien-1-yl Ester
  • Step 6 (1R,8S)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-trien-1-ol
  • Step 7 (R)-2-[(1R,8S)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yloxy]-butyric Acid Methyl Ester
  • Step 8 (R)-2-[(1R,8S)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yloxy]-butyric Acid
  • Step 9 (R)-2-[(1R,8S)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yloxy]-butyramide
  • aqueous NH 4 OH solution (28%, 46 mg, 0.75 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) was added HATU (266 mg, 0.70 mmol) and the resulting orange solution stirred at RT for 2 hours.
  • Aqueous NH 4 OH solution (28%, 23 mg, 0.38 mmol) and HATU (133 mg, 0.35 mmol) were added and the mixture stirred at RT for 75 minutes.
  • the solution was concentrated, suspended in sat. aqueous NaHCO 3 (5 mL) and water (5 mL), then extracted with CH 2 Cl 2 (2 ⁇ 10 mL).
  • EXAMPLE 2 TERT-BUTYL 3-((5R,8S)-3-(2,6-DIFLUOROPHENYL)-9,9-DIMETHYL-6,7-DIHYDRO-5,8-METHANO CINNOLIN-8(5H)-YL)PIPERAZINE-1-CARBOXYLATE AND TERT-BUTYL 2-((5R,8S)-3-(2,6-DIFLUOROPHENYL)-9,9-DIMETHYL-6,7-DIHYDRO-5,8-METHANOCINNOLIN-8(5H)-YL)PIPERAZINE-1-CARBOXYLATE
  • Step 1 2-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)-2-oxoacetaldehyde
  • Step 2 (5R,8S)-3-(2,6-Difluorophenyl)-9,9-dimethyl-8-(piperazin-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline
  • Step 3 tert-Butyl 3-((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)piperazine-1-carboxylate and tert-butyl 2-((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)piperazine-1-carboxylate
  • Step 1 ((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methyl trifluoromethanesulfonate
  • Step 2 2-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)acetonitrile
  • Step 3 2-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methano cinnolin-8(5H)-yl)-3-oxopropanenitrile
  • Step 4 Ethyl (E)-4-cyano-4-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)but-2-enoate
  • Step 5 5-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methano cinnolin-8(5H)-yl)piperidin-2-one
  • Step 1 (5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-8-((R)-piperidin-3-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline
  • Step 2 Ethyl (Z)-2-(((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methylene)butanoate
  • Step 3 Ethyl (R)-2-(((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methyl)butanoate
  • Step 4 (R)-2-(((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methyl)butanoic Acid
  • Step 5 (R)-2-(((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methyl)butanamide
  • Step 2 (S)-2-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)-N-methylmorpholine-4-carboxamide
  • Step 1 2-Bromo-1-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)ethan-1-one
  • Step 2 2-(Benzyl(2-hydroxyethyl)amino)-1-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)ethan-1-one
  • Step 3 2-(Benzyl(2-hydroxyethyl)amino)-1-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)ethan-1-ol
  • Step 4 (R)-4-Benzyl-2-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)morpholine and (S)-4-Benzyl-2-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)morpholine
  • Step 1 (S)-2-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)morpholine
  • Step 1 (S)-2-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)-N-methylmorpholine-4-carboxamide
  • This assay was used to determine a compound's potency in inhibiting activity of RORc by determining, Ki app , IC 50 , or percent inhibition values. Consumables used in this Example are shown in Table 2 below.
  • NBS Nonspecific Binding
  • TB Total Binding
  • No Receptor No R
  • 25-hydroxycholesterol (1 uM) was used to determine the level of NSB signal is prepared in DMSO as for compounds above, then diluted in Assay Buffer to give a final concentration of 5 uM.
  • 25-hydroxycholesterol in 25% DMSO/75% Assay Buffer 10 uL per well was used for NSB samples.
  • Wells for Total Binding and No Receptor sample determination contained 10 uL of 25% DMSO/75% Assay Buffer per well.
  • 25-[ 3 H]hydroxycholesterol was diluted in Assay Buffer to obtain 15 nM and vortex to mix. Add 20 uL to all wells to reach 6 nM final concentration in the assay.
  • the optimal concentration for RORc receptor was found to be 0.6 ug/mL.
  • Stock receptor solution was diluted in assay buffer to obtain 1.5 ug/mL in Assay Buffer. 20 uL was added to all wells. For No Receptor samples, 20 uL Assay Buffer was substituted for receptor solution.
  • Assay plates were 96-well polypropylene V-bottom plates. 10 uL of 5 ⁇ compound in 25% DMSO/75% Assay Buffer was added to Test wells. 10 uL of 25% DMSO/75% Assay Buffer was added to Total Binding or No Receptor wells. 10 uL of 5 uM 25-hydroxycholesterol in 25% DMSO/75% Assay Buffer was added to NSB wells. 20 uL of 15 nM 25-[ 3 H]hydroxycholesterol prepared in Assay Buffer was added to all wells. 20 uL of 1.5 ug/mL RORc receptor was added to wells (or 40 uL Assay Buffer to No R wells). Following addition to the wells, the plates were incubated 3 h at 25° C.
  • test ligand were mixed in coregulator buffer D (Invitrogen PV4420) containing 5 mM DTT and added to the plate at twice their final concentrations in a volume of 8 microL. Test ligands at 2 ⁇ the final concentration were then added to the wells in 8 ⁇ L of coregulator buffer D containing 5 mM DTT and 4% DMSO.
  • Final incubations contained 1 ⁇ coregulator buffer D, 5 mM DTT, test ligand, 2% DMSO, 50 nM biotinyl-CPSSHSSLTERKHKILHRLLQEGSPS (American Peptide Company; Vista, Calif.), 2 nM Europium anti-GST (Cisbio 61GSTKLB), 12.5 nM streptavidin-D2 (Cisbio 610SADAB), 50 mM KF, and 10 nM of bacterially-expressed human RORc ligand binding domain protein containing an N-terminal 6 ⁇ His-GST-tag and residues 262-507 of Accession NP_005051. Ten test ligand concentrations were tested in duplicate.
  • the plate was read on an EnVision plate reader (PerkinElmer) following the Europium/D2 HTRF protocol (ex 320, em 615 and 665, 100 ⁇ s lag time, 100 flashes, 500 ⁇ s window).
  • the time-resolved FRET signal at 665 nm was divided by that at 615 nm to generate the signal ratio of each well.
  • the signal ratio of wells containing RORc and peptide but no test ligand were averaged and set to 0% Effect while the signal ratios of the blank wells containing coactivator peptide but no RORc were averaged and set to ⁇ 100% Effect.
  • RORc exhibits a basal (constitutive) signal in this assay and test ligands can increase or decrease the signal ratio relative to this basal signal level.
  • RORc agonists increase the signal ratio in this assay and result in a positive % Effect value.
  • Inverse agonists decrease the signal ratio, and result in a negative % Effect value.
  • DBA/1 DBA/1OlaHsd, Harlan Laboratories mice
  • SPF pathogen free animal facility
  • Arthritis is induced by two injections of collagen subcutaneously in the base of the tail.
  • the initial injection uses bovine type II collagen (2 mg/ml from Chondrex, Redmond, Wash.) emulsified in equal volume of CFA containing 4 mg/ml of M. tuberculosis (Chondrex).
  • the CII booster injection on Day 29 is emulsified in incomplete Freund's adjuvant (IFA).
  • Each animal receives 0.1 ml of emulsion by subcutaneous/intradermal injection in the tail 2 to 3 cm from the body of the mouse.
  • the booster injection site is in the vicinity of but different from the initial injection site and closer to the body of the animal.
  • OR-1050 was formulated in HRC-6 as above. On weekdays, the animals receive two doses (a.m. and p.m.) of HRC-6 or 50 mg/kg OR-1050 p.o. (2.5 mls/kg). On weekends, a single dose of 100 mg/kg is administered (5 mls/kg).
  • mice are observed daily for clinical symptoms of CIA based on the following qualitative scale. Each paw was examined individually and scored. Grade 0, normal; grade 1, mild but definite redness and swelling of the ankle or wrist, or apparent redness and swelling limited to individual digits, regardless of the number of affected digits; grade 2, moderate redness and swelling of ankle or wrist; grade 3, severe redness and swelling of the entire paw including digits; grade 4, maximally inflamed limb with involvement of multiple joints. To estimate cumulative disease severity for each animal, an area under the curve score is calculated for each animal by totaling the sum of the daily hind paw measurements betweens days 24 and 48.
  • mice aged 4-6 weeks belong to the C57BL/6 strain weighing 17-20 g.
  • Experimental autoimmune encephalomyelitis EAE is actively induced using 95% pure synthetic myelin oligodendrocyte glycoprotein peptide 35-55 (MOG 35-55 ) (Invitrogen).
  • MOG 35-55 myelin oligodendrocyte glycoprotein peptide 35-55
  • Each mouse is anesthetized and receives 200 ug of MOG 35-55 peptide and 15 ug of Saponin extract from Quilija bark emulsified in 100 uL of phosphate-buffered saline.
  • a 25 uL volume is injected subcutaneously over four flank areas.
  • Mice are also intraperitoneally injected with 200 ng of pertussis toxin in 200 uL of PBS.
  • a second, identical injection of pertussis toxin is given after 48 h.
  • a compound of the invention is administered at selected doses.
  • Control animals receive 25 uL of DMSO.
  • Daily treatment extends from day 26 to day 36 post-immunization.
  • Clinical scores are obtained daily from day 0 post-immunization until day 60.
  • Clinical signs are scored using the following protocol: 0, no detectable signs; 0.5, distal tail limpness, hunched appearance and quiet demeanor; 1, completely limp tail; 1.5, limp tail and hindlimb weakness (unsteady gait and poor grip with hind limbs); 2, unilateral partial hind limb paralysis; 2.5, bilateral hind limb paralysis; 3, complete bilateral hindlimb paralysis; 3.5, complete hindlimb paralysis and unilateral forelimb paralysis; 4, total paralysis of hind limbs and forelimbs (Eugster et al., Eur J Immunol 2001, 31, 2302-2312).
  • Inflammation and demyelination may be assessed by histology on sections from the CNS of EAE mice. Mice are sacrificed after 30 or 60 days and whole spinal cords are removed and placed in 0.32 M sucrose solution at 4° C. overnight. Tissues are prepared and sectioned. Luxol fast blue stain is used to observe areas of demyelination. Haematoxylin and eosin staining is used to highlight areas of inflammation by darkly staining the nuclei of mononuclear cells. Immune cells stained with H&E are counted in a blinded manner under a light microscope. Sections are separated into gray and white matter and each sector is counted manually before being combined to give a total for the section.
  • T cells are immunolabeled with anti-CD3+ monoclonal antibody. After washing, sections are incubated with goat anti-rat HRP secondary antibody. Sections are then washed and counterstained with methyl green. Splenocytes isolated from mice at 30 and 60 days post-immunization are treated with lysis buffer to remove red blood cells. Cells are then re-suspended in PBS and counted. Cells at a density of about 3 ⁇ 10 6 cells/mL are incubated overnight with 20 ug/mL of MOG peptide. Supernatants from stimulated cells are assayed for IFNgamma protein levels using an appropriate mouse IFN-gamma immunoassay system.
  • mice are anesthetized with isoflurane and injected with Freund's Incomplete Adjuvant containing 1 mg/mL neuronal antigen (e.g. myelin basic protein, myelin oligodendrocyte glycoprotein, proteolipid protein) and 4 mg/mL mycobacterium tuberculosis at two sites on the back on day 0 of this study.
  • a compound of interest is then dosed daily in a sub-cutaneous, intra-peritoneally, or oral manner from day 0 until the end of study at an efficacious dose. Daily observations of degree of paralysis are taken as measures of efficacy.
  • SCID mice The severe, combined immunodeficient (SCID) mouse model can be used to evaluate the efficacy of compounds for treating psoriasis in humans (Boehncke, Ernst Schering Res Found Workshop 2005, 50, 213-34; and Bhagavathula et al., J Pharmacol Expt'l Therapeutics 2008, 324(3), 938-947). Briefly, SCID mice are used as tissue recipients. One biopsy for each normal or psoriatic volunteer (human) is transplanted onto the dorsal surface of a recipient mouse. Treatment is initiated 1 to 2 weeks after transplantation. Animals with the human skin transplants are divided into treatment groups. Animals are treated twice daily for 14 days. At the end of treatment, animals are photographed and then euthanized.
  • the transplanted human tissue along with the surrounding mouse skin is surgically removed and fixed in 10% formalin and samples obtained for microscopy. Epidermal thickness is measured. Tissue sections are stained with an antibody to the proliferation-associated antigen Ki-67 and with an anti-human CD3.sup.+ monoclonal antibody to detect human T lymphocytes in the transplanted tissue. Sections are also probed with antibodies to c-myc and beta-catenin. A positive response to treatment is reflected by a reduction in the average epiderma thickness of the psoriatic skin transplants. A positive response is also associated with reduced expression of Ki-67 in keratinocytes.
  • mice (10 males/group) received daily topical IMQ (5% cream) on shaved back and right ear for 5 days as described above. Animals received oral dose of a representative compound or DMF (45 or 90 mg-eq MMF/kg twice daily) or vehicle from Day ⁇ 5 to Day +5. Erythema score is the primary outcome measure.
  • Colonic mucosa samples are obtained and homogenized.
  • Proinflammatory mediators e.g., IL-1alpha, IL-1beta, TNFalpha, PGE2, and PGF2alpha.
  • protein concentrations are quantified.
  • Each excised large intestine is histologically examined and the damage to the colon scored.
  • mice are divided into three groups of 40 animals each. These groups are then divided into four subgroups of 10 mice each as follows: (1) no treatment/air-exposed; (2) no treatment/smoke-exposed; (3) a first dose of test compound plus smoke-exposed; and (4) a second dose of test compound.
  • trolox equivalent antioxidant capacity is assessed at the end of the exposure in bronchoalveolar lavage fluid.
  • cytokines and chemokines are determined in bronchoalveolar lavage fluid using a commercial cytokine panel at 4 hours; and in the third group bronchoalveolar lavage fluid cell count is assessed at 24 hours.
  • mice In a chronic study, the mice are exposed to either room air or to the smoke of three cigarettes/day, for 5 days/week, for 7 months. Five groups of animals are used: (1) no treatment/air-exposed; (2) a first dose of a test compound plus air-exposed; (3) no treatment/smoke-exposed; (4) a second dose of the test compound plus smoke-exposed; and (5) the first dose of the test compound plus smoke exposed. Seven months after chronic exposure to room air or cigarette smoke, 5 to 12 animals from each group are sacrificed and the lungs fixed intratracheally with formalin. Lung volume is measured by water displacement. Lungs are stained. Assessment of emphysema includes mean linear intercept and internal surface area.
  • the volume density of macrophages, marked immunohistochemically with anti-mouse Mac-3 monoclonal antibodies is determined by point counting.
  • a mouse is considered to have goblet cell metaplasia when at least one or more midsize bronchi/lung showed a positive periodic acid-Schiff staining for the determination of desmosine, fresh lungs are homogenized, processed, and analyzed by high-pressure liquid chromatography.
  • a single inhaled allergen challenge can induce an acute increase in airway responsiveness in some individuals and animal models.
  • repeated allergen inhalations have demonstrated more pronounced, consistent, and prolonged increases in airway responsiveness.
  • This mouse model of long-term repeated inhalations of allergen has been used to study the long term effect of allergic diseases in the lung, and to delineate the cells, mechanisms, molecules, and mediators involved in the induction of airway hyperresponsiveness of lung in humans.
  • Crystalline OVA is obtained from Pierce Chem. Co. (Rockford, Ill.) aluminum potassium sulfate (alum) from Sigma Chem. Co. (St. Louis, Mo.), pyrogen-free distilled water from Baxter, Healthcare Corporation (Deerfield, Ill.), 0.9% sodium chloride (normal saline) from Lymphomed (Deerfield, Ill.) and TrappsolTM.
  • HPB-L100 aqueous hydroxypropylbeta cyclodextrin; 45 wt/vol % aqueous solution) from Cyclodextrin Technologies Development, Inc. (Gainesville, Fla.).
  • the OVA 500 ug/ml in normal saline
  • the mixture pH 6.5 using 10 N NaOH
  • the selective 5-lipoxtgenase inhibitor Zileuton (N[1-benzo[b]thien-2-ylethyl]-N-hydroxyurea; J. Pharmacol Exp Ther. 1991; 256: 929-937) is dissolved in Trappsol.TM. Histatek, Inc. (Seattle, Wash.) to provide the mast cell degranulation inhibitor, f-Met-Leu-Phe-Phe (“HK-X”).
  • mice Female BALB/c Once (6-8 wk of age) receive an i.p. injection of 0.2 ml (100 ug) of OVA with alum (J. Exp Med. 1996; 184: 1483-1494). Mice are anesthetized with 0.2 ml i.p. of ketamine (0.44 mg/ml)/xylazine (6.3 mg/ml) in normal saline before receiving an intranasal (i.n.) dose of 100 ug OVA in 0.05 ml normal saline and an i.n. dose of 50 ug OVA in 0.05 ml normal saline separately on different days.
  • ketamine 0.44 mg/ml
  • xylazine 6.3 mg/ml
  • Two control groups are used: the first group receives normal saline with alum i.p. and normal saline without alum i.n.; and the second group receives OVA with alum i.p., OVA without alum i.n., and normal saline, alone.
  • the trachea and left lung (the right lung may be used for bronchoalveolar lavage (“BAL”) as described below) are obtained and fixed in 10% neutral formaldehyde solution at room temperature for about 15 h. After being embedded in paraffin, the tissues are cut into 5-um sections and processed with the different staining or immunolabling further. Discombe's eosinophil staining is used for counting the cell numbers with the counterstain of methylene blue. The eosinophil number per unit airway area (2,200 um 2 ) is determined by morphometry (J. Pathol. 1992; 166: 395-404; Am Rev Respir Dis. 1993; 147:448-456).
  • Airway mucus iss identified by the following staining method: methylene blue, hematoxylin and eosin, mucicarmine, alcian blue, and alcian blue/periodic acid-Schiff (PAS) reaction (Troyer, H., “Carbohydrates” in Principles and Techniques of Histochemistry, Little, Brown and Company, Boston, Mass., 1980: 89-121; Sheehan, D.
  • Mucin is stained with mucicarmine solution; metanil yellow counterstain is employed. Acidic mucin and sulfated mucosubstances are stained with alcian blue, pH 2.5; nuclear fast red counterstain is used. Neutral and acidic mucosubstances are identified by alcian blue, pH 2.5, and PAS reaction. The degree of mucus plugging of the airways (0.5-0.8 mm in diameter) is also assessed by morphometry. The percent occlusion of airway diameter by mucus iss classified on a semiquantitative scale from 0 to 4+. The histologic and morphometric analyses may be performed by individuals blinded to the protocol design.
  • pulmonary mechanics to intravenous infusion of methacholine may be determined in mice in vivo by a plethysmographic method as previously described (10, 1958; 192: 364-368; J. Appl. Physiol. 1988; 64: 2318-2323; J. Exp. Med. 1996; 184: 1483-1494).
  • BAL Bronchoalveolar lavage

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Abstract

Compounds of formula I:
Figure US09994551-20180612-C00001
or pharmaceutical salts thereof,
    • wherein R1, R2, R3 and R4 are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of inflammatory diseases such as arthritis.

Description

CROSS REFERENCE TO RELATED APPLICATIONS
This Application is a continuation of International Application No. PCT/EP2016/059859 filed on May 3 2016, which is entitled to the benefit U.S. Provisional Application No. 62/156,573 filed on May 4 2015 and U.S. Provisional Application No. 62/321,870 filed on Apr. 13 2016, the disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION
The invention pertains to compounds that modulate the function of retinoid-receptor related orphan receptor RORc (RORγ) and use of such compounds for treatment of autoimmune diseases
BACKGROUND OF THE INVENTION
T helper 17 cells (Th17) are interleukin (IL)-17 secreting CD4+ T cells involved in pathogenesis of autoimmune diseases such as rheumatoid arthritis, irritable bowel disease, psoriasis, psoriatic arthritis and spondyloarthridities. The retinoic acid-related orphan receptor γ (RORγ or RORc) is recognized as a transcription factor necessary for Th17 cell differentiation. RORc is an orphan member of the nuclear hormone receptor subfamily that includes RORα (RORa) and RORβ (RORb). RORc controls gene transcription by binding to DNA as a monomer. Selective modulation of RORc has been proposed as a route to discovery and development of Th17 cell-associated autoimmune diseases.
There is accordingly a need for compounds that inhibit RORc for use in treatment of autoimmune diseases such as rheumatoid arthritis, irritable bowel disease, psoriasis, psoriatic arthritis and spondyloarthridities.
SUMMARY OF THE INVENTION
The invention provides compounds of formula I:
Figure US09994551-20180612-C00002
or pharmaceutically acceptable salts thereof, wherein:
  • R1 is:
halo;
  • R2 is:
hydrogen; or
halo;
  • R3 is:
hydrogen;
C1-6alkyl; or
halo;
  • R4 is:
C1-6alkyl;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
halo-C1-6alkylsulfonyl;
aminocarbonyl-C1-6alkyl;
N-C1-6alkyl-aminocarbonyl-C1-6alkyl;
N,N-C1-6dialkyl-aminocarbonyl-C1-6alkyl;
hydroxycarbonyl-C1-6alkyl;
C1-6alkoxycarbonyl-C1-6alkyl;
C1-6alkylcarbonylamino;
—C1-6alkylene-C(O)—NRaRb wherein the C1-6alkylene- may be substituted once or twice with Rc;
C3-6cycloalkyl which may be unsubstituted or substituted once or twice with Rd;
hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with Re; or
heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Re;
  • Ra is:
hydrogen; or
C1-6alkyl;
  • Rb is:
hydrogen;
C1-6alkyl;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
C1-6alkoxy-C1-6alkyl;
C1-6alkylsulfonyl-C1-6alkyl;
C3-6cycloalkyl;
C3-6cycloalkyl-C1-6alkyl;
aminocarbonyl-C1-6alkyl;
heterocyclyl selected from: oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with Rf;
heterocyclyl-C1-6alkyl wherein the heterocycly is selected from oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with Rf;
hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; or tetrazolyl; each of which may be unsubstituted or substituted once or twice with Rg; or
heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; or tetrazolyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Rg;
or Ra and Rb together with the nitrogen atom to which they are attached may form a heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl or oxazepinyl, each may be unsubstituted or substituted once or twice with Rf;
  • Rc is:
halo;
hydroxyl; or
C3-6cycloalkyl;
  • Rd is:
C1-6alkyl;
halo;
hydroxyl; or
oxo;
  • Re is:
C1-6alkyl;
halo;
hydroxyl;
oxo;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
C1-6alkoxy-C1-6alkyl;
C1-6alkylsulfonyl-C1-6alkyl;
C3-6cycloalkyl;
C3-6cycloalkyl-C1-6alkyl;
aminocarbonyl-C1-6alkyl; or
—C(O)NHRh;
  • Rf is:
C1-6alkyl;
halo;
hydroxyl;
cyano;
oxo;
C1-6alkylsulfonyl;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
C1-6alkoxy-C1-6alkyl; or
C1-6alkylsulfonyl-C1-6alkyl;
  • Rg is:
C1-6alkyl;
hydroxyl;
hydroxy-C1-6alkyl; or
oxo;
  • Rh is:
C1-6alkyl;
hydroxy-C1-6alkyl; or
halo-C1-6alkyl.
The invention also provides and pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of preparing the compounds.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural referents unless the context clearly dictates otherwise. In some instances dashes (“-”) may be used interchangeably within definitions (for example, “alkoxyalkyl” omits the dash found in the equivalent term “alkoxy-alkyl”).
“Alkyl” means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one to six carbon atoms, i.e. C1-C6alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
“Alkenyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
“Alkynyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like.
“Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
“Alkoxy” and “alkyloxy”, which may be used interchangeably, mean a moiety of the formula —OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
“Alkoxyalkyl” means a moiety of the formula Ra—O—Rb—, where Ra is alkyl and Rb is alkylene as defined herein. Exemplary alkoxyalkyl groups include, by way of example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and 1-(2-methoxyethyl)-3-methoxypropyl.
“Alkoxyalkoxy” means a group of the formula —O—R—R′ wherein R is alkylene and R′ is alkoxy as defined herein.
“Alkylcarbonyl” means a moiety of the formula —C(O)—R, wherein R is alkyl as defined herein.
“Alkoxycarbonyl” means a group of the formula —C(O)—R wherein R is alkoxy as defined herein.
“Alkylcarbonylamino” means a group of the formula —R—C(O)—NR′— wherein R is alkyl and R′ is hydrogen or alkyl.
“Alkylcarbonylalkyl” means a group of the formula —R—C(O)—R′ wherein R is alkylene and R′ is alkyl as defined herein.
“Alkoxyalkylcarbonyl” means a moiety of the formula —C(O)—R—R′, wherein R is alkylene and R′ is alkoxy as defined herein.
“Alkoxycarbonylalkyl” means a group of the formula —R—C(O)—R′ wherein R is alkylene and R′ is alkoxy as defined herein.
“Alkoxycarbonylamino” means a moiety of the formula R—C(O)—NR′—, wherein R is alkoxy and R′ is hydrogen or alkyl as defined herein.
“Alkoxycarbonylaminoalkyl” means a moiety of the formula R—C(O)—NR′—R″—, wherein R is alkoxy, R′ is hydrogen or alkyl, and R″ is alkylene as defined herein.
“Alkoxycarbonylalkoxy”means a group of the formula —O—R—C(O)—R′ wherein R is alkylene and R′ is alkoxy as defined herein.
“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OH wherein R is alkylene as defined herein.
“Alkylaminocarbonylalkoxy” means a group of the formula —O—R—C(O)—NHR′ wherein R is alkylene and R′ is alkyl as defined herein.
“Dialkylaminocarbonylalkoxy” means a group of the formula —O—R—C(O)—NR′R″ wherein R is alkylene and R′ and R″ are alkyl as defined herein.
“Alkylaminoalkoxy” means a group of the formula —O—R—NHR′ wherein R is alkylene and R′ is alkyl as defined herein.
“Dialkylaminoalkoxy” means a group of the formula —O—R—NR′R′ wherein R is alkylene and R′ and R″ are alkyl as defined herein.
“Alkylsulfonyl” means a moiety of the formula —SO2—R, wherein R is alkyl as defined herein.
“Alkylsulfonylalkyl means a moiety of the formula —R′—SO2—R″ where where R′ is alkylene and R″ is alkyl as defined herein.
“Alkylsulfonylalkoxy” means a group of the formula —O—R—SO2—R′ wherein R is alkylene and R′ is alkyl as defined herein.
“Amino means a moiety of the formula —NRR′ wherein R and R′ each independently is hydrogen or alkyl as defined herein. “Amino thus includes “alkylamino (where one of R and R′ is alkyl and the other is hydrogen) and “dialkylamino (where R and R′ are both alkyl.
“Aminocarbonyl” means a group of the formula —C(O)—R wherein R is amino as defined herein.
“N-hydroxy-aminocarbonyl” means a group of the formula —C(O)—NR—OH wherein R is hydrogen or alkyl as defined herein.
“N-alkoxy-aminocarbonyl” means a group of the formula —C(O)—NR—R′ wherein R is hydrogen or alkyl and R′ is alkoxy as defined herein.
“Aminocarbonylaminoalkyl” means a group of the formula R2N—C(O)—NR′—R″— wherein each R is independently hydrogen or alkyl, R′ is hydrogen or alkyl, and R″ is alkylene as defined herein.
“N-alkyl-aminocarbonyl means a group of the formula —C(O)—NH—R wherein R is alkyl as defined herein.
“N-hydroxy-N-alkylaminocarbonyl means a group of the formula —C(O)—NRR′ wherein R is alkyl as defined herein and R′ is hydroxy.
“N-alkoxy-N-alkylaminocarbonyl” means a group of the formula —C(O)—NRR′ wherein R is alkyl and R′ is alkoxy as defined herein.
“N,N-di-C1-6alkyl-aminocarbonyl” means a group of the formula —C(O)—NRR′ wherein R and R′ are alkyl as defined herein.
“Aminosulfonyl” means a group of the formula —SO2—NH2.
“N-alkylaminosulfonyl” means a group of the formula —SO2—NHR wherein R is alkyl as defined herein.
“N,N-dialkylaminosulfonyl” means a group of the formula —SO2—NRR′ wherein R and R′ are alkyl as defined herein.
“Alkylsulfonylamino” means a group of the formula —NR′—SO2—R wherein R id alkyl and R′ is hydrogen or alkyl as defined herein.
“N-(alkylsulfonyl)-aminoalkyl” means a group of the formula —R—NH—SO2—R′ wherein R is alkylene and R′ is alkyl as defined herein.
“N-(Alkylsulfonyl)aminocarbonyl” means a group of the formula —C(O)—NH—SO2—R wherein wherein R is alkyl as defined herein.
“N-(Alkylsulfonyl)-N-alkylaminocarbonyl” means a group of the formula —C(O)—NR—SO2—R′ wherein R and R′ are alkyl as defined herein.
“N-Alkoxyalkyl-aminocarbonyl” means a group of the formula —C(O)—NR—R′—OR″ wherein R is hydrogen or alkyl, R′ is alkylene, and R″ is alkyl as defined herein.
“N-Hydroxyalkyl-aminocarbonyl” means a group of the formula —C(O)—NR—R′—OH″ wherein R is hydrogen or alkyl and R′ is alkylene as defined herein.
“Alkoxyamino” means a moiety of the formula —NR—OR′ wherein R is hydrogen or alkyl and R′ is alkyl as defined herein.
“Alkylsulfanyl” means a moiety of the formula —SR wherein R is alkyl as defined herein.
“Aminoalkyl” means a group —R—R′ wherein R′ is amino and R is alkylene as defined herein.
“Aminoalkyl” includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of “aminoalkyl” may be substituted once or twice with alkyl to provide “alkylaminoalkyl” and “dialkylaminoalkyl” respectively. “Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like. “Dialkylaminoalkyl” includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.
“Aminoalkoxy” means a group —OR—R′ wherein R′ is amino and R is alkylene as defined herein.
“Alkylsulfonylamido” means a moiety of the formula —NR′SO2—R wherein R is alkyl and R′ is hydrogen or alkyl.
“Aminocarbonyloxyalkyl” or “carbamylalkyl” means a group of the formula —R—O—C(O)—NR′R″ wherein R is alkylene and R′, R″ each independently is hydrogen or alkyl as defined herein.
“Alkynylalkoxy” means a group of the formula —O—R—R′ wherein R is alkylene and R′ is alkynyl as defined herein.
“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein. Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, of which may be optionally substituted as defined herein.
“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean a radical-RaRb where Ra is an alkylene group and Rb is an aryl group as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like are examples of arylalkyl.
“Arylsulfonyl means a group of the formula —SO2—R wherein R is aryl as defined herein.
“Aryloxy” means a group of the formula —O—R wherein R is aryl as defined herein.
“Aralkyloxy” means a group of the formula —O—R—R″ wherein R is alkylene and R′ is aryl as defined herein.
“Carboxy” or “hydroxycarbonyl”, which may be used interchangeably, means a group of the formula —C(O)—OH.
“Cyanoalkyl” ” means a moiety of the formula —R′—R″, where R′ is alkylene as defined herein and R″ is cyano or nitrile.
“Cycloalkyl” means a monovalent saturated carbocyclic moiety consisting of mono- or bicyclic rings. Particular cycloalkyl are unsubstituted or substituted with alkyl. Cycloalkyl can optionally be substituted as defined herein. Unless defined otherwise, cycloalkyl may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.
“Cycloalkenyl” means a cycloalkyl as defined herein that includes at least one double bond or unsaturation. Exemplary cycloalkenyl include cyclohexenyl, cyclopentenyl, cyclobutenyl and the like.
“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ is alkylene and R″ is cycloalkyl as defined herein.
“Cycloalkylalkoxy” means a group of the formula —O—R—R′ wherein R is alkylene and R′ is cycloalkyl as defined herein.
“Cycloalkylcarbonyl” means a moiety of the formula —C(O)—R, wherein R is cycloalkyl as defined herein.
“C3-6cycloalkyl-C1-6alkyl-carbonyl” means a moiety of the formula —C(O)—R, wherein R is cycloalkylalkyl as defined herein.
“Cyanoalkylcarbonyl” means a moiety of the formula —C(O)—R—R′, wherein R is alkylene as defined herein and R′ is cyano or nitrile.
“N-Cyano-aminocarbonyl” means a moiety of the formula —C(O)—NHR, wherein R is cyano or nitrile.
“N-Cyano-N-alkyl-aminocarbonyl” means a moiety of the formula —C(O)—NRR′—R, wherein R′ is alkyl as defined herein and R is cyano or nitrile.
“Cycloalkylsulfonyl” means a group of the formula —SO2—R wherein R is cycloalkyl as defined herein.
“Cycloalkylalkylsulfonyl” means a group of the formula —SO2—R wherein R is cycloalkylalkyl as defined herein.
“Formyl” means a moiety of the formula —C(O)—H.
“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like, each of which may be optionally substituted as defined herein.
Heteroarylalkyl” or “heteroaralkyl” means a group of the formula —R—R′ wherein R is alkylene and R′ is heteroaryl as defined herein.
“Heteroarylsulfonyl means a group of the formula —SO2—R wherein R is heteroaryl as defined herein.
“Heteroaryloxy” means a group of the formula —O—R wherein R is heteroaryl as defined herein.
“Heteroarylcarbonyl” means a group of the formula —C(O)—R wherein R is heteroaryl as defined herein.
“Heteroaralkyloxy” means a group of the formula —O—R—R″ wherein R is alkylene and R′ is heteroaryl as defined herein.
The terms “halo”, “halogen” and “halide”, which may be used interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.
“Haloalkyl” means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen. Exemplary haloalkyls include —CH2Cl, —CH2CF3, —CH2CCl3, perfluoroalkyl (e.g., —CF3), and the like.
“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkyl moiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.
“Heterocycloamino” means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.
“Heterocyclyl” means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl moieties include, but are not limited to, optionally substituted piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl and the like. Such heterocyclyl may be optionally substituted as defined herein.
“Heterocyclylalkyl” means a moiety of the formula —R—R′ wherein R is alkylene and R′ is heterocyclyl as defined herein.
“Heterocyclyloxy” means a moiety of the formula —OR wherein R is heterocyclyl as defined herein.
“Heterocyclylalkoxy” means a moiety of the formula —OR—R′ wherein R is alkylene and R′ is heterocyclyl as defined herein.
“Hydroxyalkoxy” means a moiety of the formula —OR wherein R is hydroxyalkyl as defined herein.
“Hydroxyalkylamino” means a moiety of the formula —NR—R′ wherein R is hydrogen or alkyl and R′ is hydroxyalkyl as defined herein.
“Hydroxyalkylaminoalkyl” means a moiety of the formula —R—NR′—R″ wherein R is alkylene, R′ is hydrogen or alkyl, and R″ is hydroxyalkyl as defined herein.
“Hydroxycarbonylalkyl” or “carboxyalkyl” means a group of the formula —R—(CO)—OH where R is alkylene as defined herein.
“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OH wherein R is alkylene as defined herein.
“Hydroxyalkylcarbonyl” means a moiety of the formula —C(O)—R—R′, wherein R is alkylene as defined herein and R′ is hydroxy.
“Hydroxyalkyloxycarbonylalkyl” or “hydroxyalkoxycarbonylalkyl” means a group of the formula —R—C(O)—O—R—OH wherein each R is alkylene and may be the same or different.
“Hydroxyalkyl” means an alkyl moiety as defined herein, substituted with one or more, for example, one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl
“Hydroxycycloalkyl” means a cycloalkyl moiety as defined herein wherein one, two or three hydrogen atoms in the cycloalkyl radical have been replaced with a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.
“Oxo” means a group of the formula ═O (i.e., an oxygen with a double bond). Thus, for example, a 1-oxo-ethyl group is an acetyl group.
“Alkoxy hydroxyalkyl” and “hydroxy alkoxyalkyl”, which may be used interchangeably, means an alkyl as defined herein that is substituted at least once with hydroxy and at least once with alkoxy.
“Alkoxy hydroxyalkyl” and “hydroxy alkoxyalkyl” thus encompass, for example, 2-hydroxy-3-methoxy-propan-1-yl and the like.
“Urea”or “ureido” means a group of the formula —NR′—C(O)—NR″R′″ wherein R′, R″ and R′″ each independently is hydrogen or alkyl.
“Carbamate” means a group of the formula —O—C(O)—NR′R″ wherein R′ and R″ each independently is hydrogen or alkyl.
“Carboxy” means a group of the formula —O—C(O)—OH.
“Sulfonamido” means a group of the formula —SO2—NR′R″ wherein R′, R″ and R′″ each independently is hydrogen or alkyl.
“Optionally substituted” when used in association with an “aryl”, phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl” moiety means that such moiety may be unsubstituted (i.e., all open valencies are occupied by a hydrogen atom) or substituted with specific groups as related herein.
“Leaving group” means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
“Modulator” means a molecule that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.
“Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
“Disease” and “Disease state” means any disease, condition, symptom, disorder or indication.
“Inert organic solvent” or “inert solvent” means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.
“Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
“Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound.
It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
“Protective group” or “protecting group” means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen and/or oxygen atoms present in the reactants. For example, the terms “amino-protecting group” and “nitrogen protecting group” are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures. Exemplary nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. The artisan in the art will know how to chose a group for the ease of removal and for the ability to withstand the following reactions.
“Solvates” means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate.
“Arthritis” means a disease or condition that causes damage to joints of the body and pain associated with such joint damage. Arthritis includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions.
“Respiratory disorder” refers to, without limitation, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.
“Subject” means mammals and non-mammals. Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like. The term “subject” does not denote a particular age or sex.
“Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
The terms “those defined above” and “those defined herein” when referring to a variable incorporates by reference the broad definition of the variable as well as particular definitions, if any.
“Treating” or “treatment” of a disease state includes, inter alia, inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, and/or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
The terms “treating”, “contacting” and “reacting” when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
Nomenclature and Structures
In general, the nomenclature and chemical names used in this Application are based on ChembioOffice™ by CambridgeSoft™. Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom unless indicated otherwise. Where a nitrogen-containing heteroaryl or heterocyclyl ring is shown with an open valency on a nitrogen atom, and variables such as Ra, Rb or Rc are shown on the heteroaryl ring, such variables may be bound or joined to the open valency nitrogen. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. Where a structure shown herein may exist in multiple tautomeric forms, all such tautomers are encompassed by the structure. The atoms represented in the structures herein are intended to encompass all naturally occurring isotopes of such atoms. Thus, for example, the hydrogen atoms represented herein are meant to include deuterium and tritium, and the carbon atoms are meant to include C13 and C14 isotopes. One or more carbon atom(s) of a compound of the invention may be replaced by a silicon atom(s), and it is contemplated that one or more oxygen atom(s) of a compound of the invention may be replaced by a sulfur or selenium atom(s).
Compounds of the Invention
The invention provides compounds of formula I:
Figure US09994551-20180612-C00003
or pharmaceutically acceptable salts thereof, wherein:
  • R1 is:
halo;
  • R2 is:
hydrogen; or
halo;
  • R3 is:
hydrogen;
C1-6alkyl; or
halo;
  • R4 is:
C1-6alkyl;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
halo-C1-6alkylsulfonyl;
aminocarbonyl-C1-6alkyl;
N-C1-6alkyl-aminocarbonyl-C1-6alkyl;
N,N-C1-6dialkyl-aminocarbonyl-C1-6alkyl;
hydroxycarbonyl-C1-6alkyl;
C1-6alkoxycarbonyl-C1-6alkyl;
C1-6alkylcarbonylamino;
—C1-6alkylene-C(O)—NRaRb wherein the C1-6alkylene- may be substituted once or twice with Rc;
C3-6cycloalkyl which may be unsubstituted or substituted once or twice with Rd;
hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with Re; or
heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Re;
  • Ra is:
hydrogen; or
C1-6alkyl;
  • Rb is:
hydrogen;
C1-6alkyl;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
C1-6alkoxy-C1-6alkyl;
C1-6alkylsulfonyl-C1-6alkyl;
C3-6cycloalkyl;
C3-6cycloalkyl-C1-6alkyl;
aminocarbonyl-C1-6alkyl;
heterocyclyl selected from: oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with Rf;
heterocyclyl-C1-6alkyl wherein the heterocycly is selected from oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with Rf;
hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; or tetrazolyl; each of which may be unsubstituted or substituted once or twice with Rg; or
heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; or tetrazolyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Rg;
or Ra and Rb together with the nitrogen atom to which they are attached may form a heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl or oxazepinyl, each may be unsubstituted or substituted once or twice with Rf;
  • Rc is:
halo;
hydroxyl; or
C3-6cycloalkyl;
  • Rd is:
C1-6alkyl;
halo;
hydroxyl; or
oxo;
  • Re is:
C1-6alkyl;
halo;
hydroxyl;
oxo;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
C1-6alkoxy-C1-6alkyl;
C1-6alkylsulfonyl-C1-6alkyl;
C3-6cycloalkyl;
C3-6cycloalkyl-C1-6alkyl;
aminocarbonyl-C1-6alkyl; or
—C(O)NHRh;
  • Rf is:
C1-6alkyl;
halo;
hydroxyl;
cyano;
oxo;
C1-6alkylsulfonyl;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
C1-6alkoxy-C1-6alkyl; or
C1-6alkylsulfonyl-C1-6alkyl;
  • Rg is:
C1-6alkyl;
hydroxyl;
hydroxy-C1-6alkyl; or
oxo;
  • Rh is:
C1-6alkyl;
hydroxy-C1-6alkyl; or
halo-C1-6alkyl.
In certain embodiments, R1 is fluoro.
In certain embodiments, R2 is hydrogen.
In certain embodiments, R2 is halo.
In certain embodiments, R2 is fluoro.
In certain embodiments, R3 is hydrogen.
In certain embodiments, R3 is halo.
In certain embodiments, R3 is C1-6alkyl.
In certain embodiments, R4 is:
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
halo-C1-6alkylsulfonyl;
aminocarbonyl-C1-6alkyl;
C1-6alkylcarbonylamino;
—C1-6alkylene-C(O)—NRaRb wherein the C1-6alkylene- may be substituted once or twice with Rc;
C3-6cycloalkyl which may be unsubstituted or substituted once or twice with Rd;
hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with Re; or
heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Re.
In certain embodiments, R4 is:
aminocarbonyl-C1-6alkyl;
C1-6alkylcarbonylamino;
—C1-6alkylene-C(O)—NRaRb wherein the C1-6alkylene- may be substituted once or twice with Rc;
C3-6cycloalkyl which may be unsubstituted or substituted once or twice with Rd;
hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with Re; or
heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Re.
In certain embodiments, R4 is:
—C1-6alkylene-C(O)—NRaRb wherein the C1-6alkylene- may be substituted once or twice with Rc;
C3-6cycloalkyl which may be unsubstituted or substituted once or twice with Rd;
hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with Re; or
heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Re.
In certain embodiments, R4 is:
hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with Re; or
heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Re.
In certain embodiments, R4 is C1-6alkyl.
In certain embodiments, R4 is halo-C1-6alkyl.
In certain embodiments, R4 is hydroxy-C1-6alkyl.
In certain embodiments, R4 is halo-C1-6alkylsulfonyl.
In certain embodiments, R4 is aminocarbonyl-C1-6alkyl.
In certain embodiments, R4 is C1-6alkylcarbonylamino.
In certain embodiments, R4 is hydroxycarbonyl-C1-6alkyl;
In certain embodiments, R4 is C1-6alkoxycarbonyl-C1-6alkyl;
In certain embodiments, R4 is —C1-6alkylene-C(O)—NRaRb wherein the C1-6alkylene- may be substituted once or twice with Rc.
In certain embodiments, R4 is C3-6cycloalkyl which may be unsubstituted or substituted once or twice with Rd.
In certain embodiments, R4 is hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with Re.
In certain embodiments, R4 is heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Re.
In certain embodiments, Ra is hydrogen.
In certain embodiments, Ra is C1-6alkyl.
In certain embodiments, Rb is hydrogen.
In certain embodiments, Rb is C1-6alkyl.
In certain embodiments, Rb is halo-C1-6alkyl.
In certain embodiments, Rb is hydroxy-C1-6alkyl.
In certain embodiments, Rb is C1-6alkoxy-C1-6alkyl.
In certain embodiments, Rb is C1-6alkylsulfonyl-C1-6alkyl.
In certain embodiments, Rb is C3-6cycloalkyl.
In certain embodiments, Rb is C3-6cycloalkyl-C1-6alkyl.
In certain embodiments, Rb is aminocarbonyl-C1-6alkyl.
In certain embodiments, Rb is heterocyclyl selected from: oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with Rf.
In certain embodiments, Rb is heterocyclyl-C1-6alkyl wherein the heterocycly is selected from oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with Rf.
In certain embodiments, Rb is hetereoaryl selected from oxazolyl. isoxazolyl. oxadiazolyl. triazolyl. pyrrolyl. pyrazolyl. imidazolyl. or tetrazolyl. each of which may be unsubstituted or substituted once or twice with Rg.
In certain embodiments, Rb is heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl. isoxazolyl. oxadiazolyl. triazolyl. pyrrolyl. pyrazolyl. imidazolyl. or tetrazolyl. wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Rg.
In certain embodiments, Ra and Rb together with the nitrogen atom to which they are attached may form a heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl or oxazepinyl, each may be unsubstituted or substituted once or twice with Rf.
In certain embodiments, Rc is halo.
In certain embodiments, Rc is hydroxyl.
In certain embodiments, Rc is C3-6cycloalkyl.
In certain embodiments, Rd is C1-6alkyl.
In certain embodiments, Rd is halo.
In certain embodiments, Rd is hydroxyl.
In certain embodiments, Rd is oxo.
In certain embodiments, Re is C1-6alkyl.
In certain embodiments, Re is halo.
In certain embodiments, Re is hydroxyl.
In certain embodiments, Re is oxo.
In certain embodiments, Re is halo-C1-6alkyl.
In certain embodiments, Re is hydroxy-C1-6alkyl.
In certain embodiments, Re is C1-6alkoxy-C1-6alkyl.
In certain embodiments, Re is C1-6alkylsulfonyl-C1-6alkyl.
In certain embodiments, Re is C3-6cycloalkyl.
In certain embodiments, Re is C3-6cycloalkyl-C1-6alkyl.
In certain embodiments, Re is aminocarbonyl-C1-6alkyl.
In certain embodiments, Re is —C(O)NHRh.
In certain embodiments, Rf is C1-6alkyl.
In certain embodiments, Rf is halo.
In certain embodiments, Rf is hydroxyl.
In certain embodiments, Rf is cyano.
In certain embodiments, Rf is oxo.
In certain embodiments, Rf is C1-6alkylsulfonyl.
In certain embodiments, Rf is halo-C1-6alkyl.
In certain embodiments, Rf is hydroxy-C1-6alkyl.
In certain embodiments, Rf is C1-6alkoxy-C1-6alkyl.
In certain embodiments, Rf is C1-6alkylsulfonyl-C1-6alkyl.
In certain embodiments, Rg is C1-6alkyl.
In certain embodiments, Rg is hydroxyl.
In certain embodiments, Rg is hydroxy-C1-6alkyl.
In certain embodiments, Rg is oxo.
In certain embodiments, Rh is C1-6alkyl.
In certain embodiments, Rh is hydroxy-C1-6alkyl.
In certain embodiments, Rh is halo-C1-6alkyl.
In certain embodiments, the compounds of the invention may be of formula Ia or Ib
Figure US09994551-20180612-C00004
wherein R1, R2 and R4 are as defined herein.
In certain embodiments, the compounds of the invention are of formula Ia.
In certain embodiments, the compounds of the invention are of formula Ib.
In certain embodiments, the compounds of the invention are of formula II
Figure US09994551-20180612-C00005
or pharmaceutically acceptable salts thereof, wherein:
  • m is: 0; or 1;
  • n is: 0; or 1;
  • p is: 0; 1; or 2;
  • q is: 0; or 1;
  • X is: C; O; or N;
  • Y is: C; O; or N;
  • R1 is:
halo;
  • R2 is:
hydrogen; or
halo;
  • R3 is:
hydrogen;
C1-6alkyl; or
halo;
  • R5 is:
C1-6alkyl; or
oxo;
  • R6 is:
C1-6alkyl;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
benzyl;
C1-6alkoxycarbonyl;
C1-6alkylcarbonyl;
C1-6alkylsulfonyl;
aminocarbonyl;
—C(O)—NRjRk;
aminosulfonyl;
hydroxy-C1-6alkylcarbonyl;
heteroaryl selected from: pyridinyl; pyrimidinyl; pyridazinyl; pyrazinyl; oxadiazolyl; oxazoyl; oxazolidinyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with Ri;
heteroarylcarbonyl wherein the heteroaryl portion is selected from: pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; oxadiazolyl; oxazoyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with Ri;
heteroaryl-C1-6alkyl wherein the heteroaryl portion is selected from: pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; oxadiazolyl; oxazoyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with R′;
  • Ri is:
C1-6alkyl;
halo-C1-6alkyl;
C1-6alkoxycarbonyl;
benzyl;
halo;
hydroxyl;
hydroxy-C1-6alkyl; or
oxo;
  • Rj is:
hydrogen; or
C1-6alkyl; and
  • Rk is:
hydrogen;
C1-6alkyl;
hydroxy-C1-6alkyl;
C3-6cycloalkyl which may be unsubstituted or substituted once or twice with Ri;
C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl portion may be unsubstituted or substituted once or twice with Ri
heterocyclyl selected from oxetanyl and azetedinyl which may be unsubstituted or substituted once or twice with Ri; or
heterocyclyl-C1-6alkyl wherein the heterocyclyl portion is selected from oxetanyl and azetedinyl and may be unsubstituted or substituted once or twice with Ri.
In certain embodiments,
In certain embodiments, m is: 0.
In certain embodiments, m is: 1.
In certain embodiments, n is: 0.
In certain embodiments, n is: 1.
In certain embodiments, p is: 0.
In certain embodiments, p is: 1.
In certain embodiments, p is: 2.
In certain embodiments, p is: 0 or 1.
In certain embodiments, q is: 0.
In certain embodiments, q is: 1.
In certain embodiments, X is C.
In certain embodiments, X is O.
In certain embodiments, X is N.
In certain embodiments, Y is C.
In certain embodiments, Y is O.
In certain embodiments, Y is N.
In certain embodiments, R1 is fluoro.
In certain embodiments, R2 is hydrogen.
In certain embodiments, R2 is halo.
In certain embodiments, R2 is fluoro.
In certain embodiments, R3 is hydrogen.
In certain embodiments, R3 is halo.
In certain embodiments, R3 is C1-6alkyl.
In certain embodiments, R5 is C1-6alkyl;.
In certain embodiments, R5 is oxo.
In certain embodiments, R6 is C1-6alkyl.
In certain embodiments, R6 is halo-C1-6alkyl.
In certain embodiments, R6 is hydroxy-C1-6alkyl.
In certain embodiments, R6 is benzyl.
In certain embodiments, R6 is C1-6alkoxycarbonyl.
In certain embodiments, R6 is C1-6alkylcarbonyl.
In certain embodiments, R6 is C1-6alkylsulfonyl.
In certain embodiments, R6 is aminocarbonyl;.
In certain embodiments, R6 is hydroxy-C1-6alkylcarbonyl.
In certain embodiments, R6 is heteroaryl selected from: pyridinyl; pyrimidinyl; pyrazinyl; oxadiazolyl; oxazoyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with Ri.
In certain embodiments, R6 is heteroarylcarbonyl wherein the heteroaryl portion is selected from: pyridinyl; pyrimidinyl; pyrazinyl; oxadiazolyl; oxazoyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with Ri.
In certain embodiments, R6 is heteroaryl-C1-6alkyl wherein the heteroaryl portion is selected from: pyridinyl; pyrimidinyl; pyrazinyl; oxadiazolyl; oxazoyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with Ri.
  • In certain embodiments, Ri is
In certain embodiments, Ri is C1-6alkyl.
In certain embodiments, Ri is halo-C1-6alkyl.
In certain embodiments, Ri is hydroxy-C1-6alkyl.
In certain embodiments, Ri is oxo.
In certain embodiments, the compounds of the invention may be of formula IIa or IIb
Figure US09994551-20180612-C00006
wherein m, n, R1, R2, R5 and R6 are as defined herein.
In certain embodiments, the compounds of the invention are of formula IIa.
In certain embodiments, the compounds of the invention are of formula IIb.
In certain embodiments, the compounds of the invention are of formula III
Figure US09994551-20180612-C00007
wherein m, n, R1, R2, R5 and R6 are as defined herein.
In certain embodiments, the compounds of the invention are of formula IIIa, IIb, IIIc or IIId
Figure US09994551-20180612-C00008
In certain embodiments, the compounds of the invention are of formula IIIa.
In certain embodiments, the compounds of the invention are of formula IIIb.
In certain embodiments, the compounds of the invention are of formula IIIc.
In certain embodiments, the compounds of the invention are of formula IIId.
In certain embodiments, the compounds of the invention are of formula IV
Figure US09994551-20180612-C00009
wherein m, n, R1, R2, R5 and R6 are as defined herein.
In certain embodiments, the compounds of the invention are of formula IIIa, IIb, IIIc or IIId
Figure US09994551-20180612-C00010
In certain embodiments, the compounds of the invention are of formula IVa.
In certain embodiments, the compounds of the invention are of formula IVb.
In certain embodiments, the compounds of the invention are of formula IVc.
In certain embodiments, the compounds of the invention are of formula IVd.
In certain embodiments, the compounds of the invention are of formula V
Figure US09994551-20180612-C00011
wherein m, n, R1, R2, R5 and R6 are as defined herein.
In certain embodiments, the compounds of the invention are of formula IIIa, IIb, IIIc or IIId
Figure US09994551-20180612-C00012
In certain embodiments, the compounds of the invention are of formula Va.
In certain embodiments, the compounds of the invention are of formula Vb.
In certain embodiments, the compounds of the invention are of formula Vc.
In certain embodiments, the compounds of the invention are of formula Vd.
Methods
The invention also provides a method for treating a disease or condition mediated by or otherwise associated with the RORc receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention.
The disease may be arthritis such as rheumatoid arthritis or osteoarthritis.
The disease may be asthma or COPD.
The disease may be psoriasis.
The disease may be muscular distrophy.
Representative compounds in accordance with the methods of the invention are shown in the experimental examples below.
Synthesis
Compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below.
The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.
The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein may be conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about −78° C. to about 150° C., for example, from about 0° C. to about 125° C., or conveniently at about room (or ambient) temperature, e.g., about 20° C.
Scheme A below illustrates one synthetic procedure usable to prepare specific compounds of formula I, wherein X is halo or other leaving group and R1, R2, R4 and R5 are as defined herein.
Figure US09994551-20180612-C00013
Figure US09994551-20180612-C00014
In step 1 of Scheme A, fenchone compound a is reacted with trifluoromethanesulfonyl anhydride to yield an unsaturated trifluoromethanesulfonyl ester compound b. In step 2 compound b undergoes a first oxidation to form a camphor trifluoromethanesulfonyl ester compound c. The oxidation of step 2 may be carried out using ozonation. A second oxidation is made in step 3, using selenium dioxide, to provide a dioxo trifluoromethanesulfonyl ester compound d. In step 4, compound d undergoes reaction with aryl ketophosphonate ester e to give compound f. In step 5, compound f is reacted with hydrazine to to give cinnoline trifluoromethanesulfonyl ester compound g. Compound g undergoes hydrolysis in step 6 to yield the corresponding hydroxy-cinnoline compound h. An O-alkylation is then carried out in step 7 by reaction with alkylating agent i to give cinnoline ether compound j, which is a compound of formula I in accordance with the invention.
Many variations on the procedures of Scheme A are possible and will suggest themselves to those skilled in the art. Specific details for producing compounds of the invention are described in the Examples below.
Administration and Pharmaceutical Composition
The invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
In general, the compounds of the invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, for example 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
Compounds of the invention may be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. A particular manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
A compound or compounds of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of the invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component. The pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets may contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
The compounds of the invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The compounds of the invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
The subject compounds may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatine or blister packs from which the powder may be administered by means of an inhaler.
When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylazacycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
The pharmaceutical preparations may be in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa. Representative pharmaceutical formulations containing a compound of the present invention are described below.
Utility
The compounds of the invention are useful for treatment of immune disorders generally. The compounds may be used for treatment of arthritis, including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, and other arthritic conditions.
The compounds may be used for treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and the like.
The compounds may be used for treatment of gastrointestinal disorder (“GI disorder”) such as Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, pain associated with GI distension, and the like.
The compounds may be used for treatment of pain conditions such as inflammatory pain; arthritic pain, surgical pain; visceral pain; dental pain; premenstrual pain; central pain; pain due to burns; migraine or cluster headaches; nerve injury; neuritis; neuralgias; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infection; post-traumatic injury; or pain associated with irritable bowel syndrome.
The compounds may be used for treatment of muscular sclerosis, Sjogren's disease, lupus, and pulmonary fibrosis.
The compounds may be used for treatment of cancer and inhibition or tumor growth, including prostate cancer and castrate-resistant prostate cancer.
General Experimental
LCMS Methods:
High Pressure Liquid Chromatography-Mass Spectrometry (LCMS) experiments to determine retention times (RT) and associated mass ions were performed using one of the following methods:
Method A: Compounds were analyzed using the following conditions: Experiments were performed on a Waters ZMD single quadrupole mass spectrometer linked to a Hewlett-Packard HP1100 LC system with UV diode array detector and 100 position autosampler. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses a Phenomenex Luna 3 μm C18(2) 30×4.6 mm column at ambient temperature and a 2.0 mL/minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. This was maintained for 1 minute before returning to 95% solvent A and 5% solvent B over the next 0.5 minute. Total run time was 6 minutes.
Method B: Compounds were analysed using the following conditions: Experiments were performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses an Acquity BEH C18 1.7 μm 100×2.1 mm column, maintained at 40° C. or an Acquity BEH Shield RP18 1.7 μm 100×2.1 mm column, maintained at 40° C. and a 0.4 mL/minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.4 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 5.6 minutes. This was maintained for 0.8 minute before returning to 95% solvent A and 5% solvent B over the next 1.2 minutes. Total run time was 8 minutes.
NMR Methods:
1H NMR spectra were recorded at ambient temperature or at 80° C. where indicated using one of the following machines: Varian Unity Inova (400 MHz) spectrometer with a triple resonance 5 mm probe, Bruker Avance DRX 400 (400 MHz) spectrometer with a triple resonance 5 mm probe, a Bruker Avance DPX 300 (300 MHz) equipped with a standard 5 mm dual frequency probe for detection of 1H and 13C, Bruker Fourier 300 MHz system equipped with a standard 5 mm 1H/13C probe, a Bruker AVIII (400 MHz) using a BBI Broad Band Inverse 5 mm probe, or a Bruker AVIII (500 MHz) using a QNP (Quad Nucleus detect) 5 mm probe. Chemical shifts are expressed in ppm relative to an internal standard, tetramethylsilane (ppm=0.00). The following abbreviations have been used: br=broad signal, s=singlet, d=doublet, dd=double doublet, t=triplet, td=triplet doublet, dddd=doublet doublet doublet doublet, q=quartet, m=multiplet, or any combination thereof.
Microwave Reactor:
Microwave reactions were carried out using a Biotage® Initiator® in vials appropriate to the scale of the reaction and at the temperature and time described in the experimental details.
Purification Equipment:
Purifications were carried out using pre-packed silica gel cartridges either on a Teledyne ISCO CombiFlash® or Biotage® Isolera Four® or using compressed air to apply external pressure. Solvents and gradients shown in the experimental details were used.
Reverse Phase High Pressure Liquid Chromatography (HPLC) was used to purify compounds where indicated. Separation using gradient elution on a Phenomenex Gemini C18 column (250×21.2 mm, 5 μm) as stationary phase and using mobile phase indicated, operating at a 18 mL/min flow rate using a Gilson UV/Vis-155 dual channel detector and Gilson GX-271 automated liquid handler.
Mass-directed auto-purification (MDAP) was used to purify compounds where indicated. An Agilent 1260 infinity purifications system with Agilent 6100 series single Quadrupole LC/MS and XSEELECT CSH Prep C18 5 μm OBD, 30×150 mm column at RT was used. The mobile phases were 0.1% aqueous formic acid and 0.1% formic acid in acetonitrile, flowing at 60 ml/min, with a 10%-95% gradient, over 22 min, with a specific focused gradient.
Phase separator cartridges are supplied by Biotage® as Isolute® phase separator cartridges.
List of Abbreviations
  • AcOH Acetic acid
  • AIBN 2,2′-Azobis(2-methylpropionitrile)
  • Atm. Atmosphere
  • BOC tert-Butyloxycarbonyl group
  • (BOC)2O Di-tert-butyl dicarbonate
  • CrO3 Chromium(VI) oxide
  • CDCl3 Deuterated chloroform
  • DavePhos 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl
  • DCM Dichloromethane/methylene chloride
  • DMA N,N-Dimethylacetamide
  • DIAD Diisopropyl azodicarboxylate
  • DIPEA Diisopropylethylamine
  • DMAP 4-Dimethylaminopyridine
  • DME 1,2-Dimethoxyethane
  • DMF N,N-Dimethylformamide
  • DMSO Dimethyl sulfoxide
  • DPPF 1,1′-Bis(diphenylphosphino)ferrocene
  • ES Electrospray
  • Et2O Diethyl ether
  • Et3N Triethylamine
  • EtOH Ethanol/Ethyl alcohol
  • EtOAc Ethyl acetate
  • H2O Water
  • H2SO4 Sulfuric acid
  • HATU 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium
  • HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • HCO2H Formic acid
  • HCl Hydrochloric acid
  • HOBT 1-Hydroxybenzotriazole
  • HPLC High pressure liquid chromatography
  • RP HPLC Reverse phase high pressure liquid chromatography
  • IBX 2-Iodoxybenzoic acid
  • IMS Industrial methylated spirit
  • KOH Potassium hydroxide
  • K2CO3 Potassium carbonate
  • LDA Lithium diisopropylamide
  • i-PrOH Isopropanol/isopropyl alcohol/propan-2-ol
  • LCMS Liquid Chromatograph/Mass Spectroscopy
  • LiOH Lithium hydroxide
  • MDAP Mass-directed auto-purification
  • MgSO4 Magnesium sulphate
  • MeOH Methanol/Methyl alcohol
  • MW Microwaves
  • NaH Sodium hydride
  • NaCl Sodium chloride
  • NaOH Sodium hydroxide
  • Na2SO4 Sodium sulfate
  • Na2CO3 Sodium carbonate
  • NaHCO3 Sodium bicarbonate/Sodium hydrogen carbonate
  • NBS N-Bromosuccinimide
  • NH4Cl Ammonium chloride
  • NMP 1-Methyl-2-pyrrolidinone
  • POCl3 Phosphorus oxychloride
  • PhCH3 Toluene
  • Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)
  • PSI Pound per square inch
  • RT Room temperature
  • sat. Saturated
  • SCX-2 Pre-packed Isolute® silica-based sorbent with a chemically bonded propylsulfonic acid functional group
  • TBDMS tert-Butyldimethylsilyl
  • TFA Trifluoroacetic acid
  • THF Tetrahydrofuran
  • TIPS Triisopropylsilyl
  • TLC Thin layer chromatography
  • XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
Intermediate A: (1R)-5-(2,6-Fluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene-1-carboxylic Acid
Figure US09994551-20180612-C00015
Step 1: 2-(2,6-Difluorophenyl)-2-oxoacetaldehyde
A mixture of selenium dioxide (111 g, 1000 mmol) in 1,4-dioxane/H2O (500 mL/20 mL) at 55° C. was stirred for 30 min and then added 1-(2,6-difluorophenyl)ethanone (156 g, 1000 mmol). The mixture was refluxed for 20 h. The reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by fractional distillation collecting the fractions between 90-94° C., under vacuum (˜1 mm mercury), to afford the title compound as yellow oil (98.5 g). 1H NMR (500 MHz, DMSO-d6): δ 9.48 (t, J=2.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.33-7.29 (m, 2H); MS (ESI): [M+H]+ 171.
Step 2: Methyl (1R)-3-[2-(2,6-difluorophenyl)-2-oxoethylidene]-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate and (1R)-methyl 3-(2-(2,6-difluorophenyl)-1-hydroxy-2-oxoethyl)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate
A solution of (1R)-methyl 7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate (19.6 g, 100 mmol) in anhydrous THF (100 mL) at −78° C. under nitrogen was added LDA (75 mL, 2 M in THF) dropwise. The mixture was stirred at −78° C. for 1 h, and then 2-(2,6-difluorophenyl)-2-oxoacetaldehyde (20.4 g, 120 mmol) in THF (50 mL) was added. The mixture was stirred at −78° C. for 1 hour and allowed to warm to room temperature. The reaction mixture was quenched with 1 N aqueous HCl (100 mL) and concentrated under reduced pressure. The residue was extracted with EtOAc (100 mL×3). The combined organic layers were concentrated under reduced pressure and the residue was purified by chromatography (1:30 EtOAc in petroleum ether) to afford the title compounds as yellow solids: methyl (1R)-3-[2-(2,6-difluorophenyl)-2-oxoethylidene]-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate, (2.12 g), 1H NMR (500 MHz, DMSO-d6): δ 7.72-7.66 (m, 1H), 7.29-7.26 (m, 2H), 6.99 (s, 1H), 3.72 (s, 3H), 3.30-3.29 (m, 1H), 2.45-2.39 (m, 1H), 2.24-2.17 (m, 1H), 1.79-1.74 (m, 1H), 1.43-1.38 (m, 1H), 1.07 (s, 3H), 1.03 (s, 3H); MS (ESI): [M+H]+ 349.1; (1R)-methyl 3-(2-(2,6-difluorophenyl)-1-hydroxy-2-oxoethyl)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate, (5.51 g), 1H NMR (500 MHz, DMSO-d6): δ 7.65-7.58 (m, 1H), 7.24-7.20 (m, 2H), 6.27 (d, J=7.5 Hz, 1H), 4.63-4.60 (m, 1H), 3.66 (s, 3H), 2.28-2.23 (m, 1H), 2.04-1.97 (m, 2H), 1.87-1.81 (m, 1H), 1.51-1.46 (m, 1H), 1.89 (s, 3 H), 0.99 (s, 3H); MS (ESI): [M+H]+ 367.1.
Step 3: Methyl (1R)-5-(2,6-fluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene-1-carboxylate
A mixture of methyl (1R)-3-[2-(2,6-difluorophenyl)-2-oxoethylidene]-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylate (2.09 g, 6.0 mmol) and hydrazine hydrochloride (4.08 g, 60 mmol) in butan-1-ol (100 mL) was heated at 135° C. for 20 h. The reaction mixture was concentrated under reduced pressure, the residue dissolved in H2O (100 mL) and extracted with EtOAc (20 mL×3). The combined organic fractions were concentrated under reduced pressure and the residue was purified by chromatography (3:1 petroleum ether-EtOAc) to afford the title compound as yellow solid (1.78 g). MS (ESI): [M+H]+ 345.1.
Following the procedure described above and starting with (1R)-methyl 3-(2-(2,6-difluorophenyl)-1-hydroxy-2-oxoethyl)-7,7-dimethyl-2-oxobicyclop.2.2.1heptane-1-carboxylate (5.49 g, 15 mmol), the title compound was obtained as a yellow solid (4.39 g). MS (ESI): [M+H]+ 345.1.
Step 4: (1R)-5-(2,6-Fluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene-1-carboxylic Acid
A mixture of the product from Step 3 (5.16 g, 15 mmol) and LiOH monohydrate (0.84 g, 63.5 mmol) in THF/H2O (50 mL/5 mL) was heated at 30° C. for 20 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in H2O (100 mL) and 1N aqueous HCl added slowly until pH 3 was achieved. The mixture was extracted with EtOAc (20 mL×3) and the combined organic fractions were concentrated under reduced pressure to afford the title compound as a yellow solid (4.21 g). 1H NMR (500 MHz, DMSO-d6): δ 12.88 (s, 1H), 7.75 (s, 1H), 7.65-7.59 (m, 1H), 7.32-7.29 (m, 1H), 3.16-3.15 (m, 1H), 2.61-2.54 (m, 1H), 2.32-2.27 (m, 1H), 1.52-1.47 (m, 1H), 1.18-1.13 (m, overlap, 4H), 0.79 (s, 3H); MS (ESI): [M+H]+ 331.1.
Intermediate B: [(1R,8R)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yl]-methanol
Figure US09994551-20180612-C00016
Isobutyl chloroformate (55 mg, 0.4 mmol) was added to a stirred, ice-cooled solution of (1R)-5-(2,6-fluorophenyl)-11,11-dimethyl-3,4-diazatricyclo[6.2.1.02,7]undeca-2(7),3,5-triene-1-carboxylic acid (110 mg, 0.33 mmol) and triethylamine (51 mg, 0.5 mmol) in THF (5 mL) and stirred for 15 min before being filtered and concentrated in vacuo. The residue was dissolved in EtOH (5 mL) and sodium borohydride (19 mg, 0.5 mmol) was added with stirring and cooling in ice. After 1 h the solution was concentrated in vacuo and the residue dissolved in EtOAc and H2O and the organic phase dried (Na2SO4), filtered, and the filtrate concentrated in vacuo to afford the title compound as a white solid (101 mg). MS (ESI): [M+H]+ 317.0.
Intermediate C: 1-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)ethan-1-one
Figure US09994551-20180612-C00017
Step 1: (5R,8R)-3-(2,6-Difluorophenyl)-N-methoxy-N,9,9-trimethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxamide
To a solution of (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxylic acid (11.0 g, 33.3 mmol) in CH2Cl2 (250 mL) was added oxalyl chloride (4.2 mL, 49.97 mmol) and DMF (0.2 mL). The mixture was stirred at room temperature for 1 h, concentrated in vacuo, and DCM (250 mL) and Et3N (9.3 mL, 66.6 mmol) were added. The mixture was cooled to 0° C. and N,O-dimethylhydroxylamine hydrochloride (3.25 g, 43.30 mmol) was added in portions. The mixture was allowed to warm up to room temperature and stirred for 40 min, quenched with saturated aqueous NH4Cl (100 mL). The organic phase was seperated, dried (Na2SO4), filtered and purified by chromatography (0-50% EtOAc-petroleum ether) to give the title compound as a yellow solid (12.1 g). LCMS (ESI): m/z=374.2 [M+H]+.
Step 2: 1-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)ethan-1-one
To a solution of (5R,8R)-3-(2,6-difluorophenyl)-N-methoxy-N,9,9-trimethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carboxamide (12.1 g, 32.4 mmol) in dry THF (100 mL) at 0° C. under a nitrogen atmosphere was added dropwise methylmagnesium bromide (3 M in Et2O, 16.2 mL, 48.61 mmol). The mixture was stirred at room temperature for 0.5 h, quenched with saturated aqueous NH4Cl (150 mL) and extracted with EtOAc (2×150 mL), dried (Na2SO4) and purified by chromatography (0-37% EtOAc-petroleum ether) to give the title compound as a yellow solid (8.4 g). LCMS (ESI): m/z=329.2 [M+H]+.
EXAMPLE 1: (R)-2-[(1R,8S)-5-(2,6-DIFLUORO-PHENYL)-11,11-DIMETHYL-3,4-DIAZA-TRICYCLO[6.2.1.0*2,7*]UNDECA-2(7),3,5-TRIEN-1-YLOXY]-BUTYRAMIDE
Figure US09994551-20180612-C00018
Figure US09994551-20180612-C00019
Step 1: Trifluoro-methanesulfonic Acid (1S,4S)-7,7-dimethyl-2-methylene-bicyclo[2.2.1]hept-1-yl Ester
A solution of (−)-fenchone (15.2 g, 100 mmol) and tri-iso-butylamine (61 mL, 250 mmol) in CH2Cl2 (200 mL) was cooled to 0° C. and treated dropwise with trifluoromethanesulfonic anhydride (34 mL, 200 mmol) over 1 h. The reaction was stirred for 65 h, concentrated in vacuo and the residue immediately stirred rapidly with cyclohexanes. The solids were collected by filtration and the filtrate concentrated. Purification by chromatography (100% pentane) gave the title compound as a yellow oil (7.22 g). 1H NMR (300 MHz, CDCl3): δ 5.20-5.17 (m, 1H), 4.95-4.92 (m, 1H), 2.65-2.43 (m, 2H), 2.21-2.04 (m, 3H), 1.84-1.77 (m, 1H), 1.54-1.50 (m, 1H), 1.12 (s, 3H), 1.00 (s, 3H).
Step 2: Trifluoro-methanesulfonic Acid (1R,4S)-7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-yl Ester
A solution of the product from step 1 (7.22 g, 25.4 mmol) in CH2Cl2 (140 mL) was cooled to −78° C. and ozone was bubbled through and the reaction. Dimethylsulfide (4.72 g, 3 eq, 5.6 mL) was added after 7 h and the reaction allowed to warm to room temperature overnight. The reaction was concentrated in vacuo, partitioned between H2O-cyclohexanes, dried (Na2SO4), and concentrated in vacuo. Purification by chromatography (0-40% EtOAc-heptane) gave the title compound and recovered starting material. The reaction was repeated using the recovered starting material to give the title compound (4.74 g). 1H NMR (300 MHz, CDCl3): δ 2.58 (ddd, J=2.5, 5.1, 18.8 Hz, 1H), 2.36-2.10 (m, 4H), 1.73-1.61 (m, 2H), 1.17 (s, 3H), 1.05 (s, 3H).
Step 3: Trifluoro-methanesulfonic acid (1R,4R)-7,7-dimethyl-2,3-dioxo-bicyclo[2.2.1]hept-1-yl Ester
A mixture of the product from step 2 (1.47 g, 5.13 mmol) and selenium dioxide (1.14 g, 5.13 mmol) in bromobenzene (10 mL) was heated at 160° C. for 4 h. The reaction was cooled, diluted with EtOAc (10 mL) and filtered through diatomaceous earth. The filter pad was washed with EtOAc (10 mL) and the combined organic washes concentrated in vacuo. Purification by chromatography (10-30% EtOAc-cyclohexanes) gave the title compound as a crystalline yellow solid (900 mg). 1H NMR (300 MHz, CDCl3): δ 2.83-2.80 (m, 1H), 2.54-2.37 (m, 2H), 1.76-1.68 (m, 2H), 1.25 (s, 3H), 1.11 (s, 3H).
Step 4: Trifluoro-methanesulfonic Acid (1R,4R)-3-[2-(2,6-difluoro-phenyl)-2-oxo-eth-(Z)-ylidene]-7,7-dimethyl-2-oxo-bicyclo[2.2.1]hept-1-yl ester and trifluoro-methanesulfonic Acid (1R,4R)-3-[2-(2,6-difluoro-phenyl)-2-oxo-eth-(E)-ylidene]-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl Ester
A solution of the [2-(2,6-difluoro-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (984 mg, 3.73 mmol) and potassium tert-butoxide (419 mg) in tert-butanol (20 mL) was stirred at room temperature for 30 min and then added to a suspension of the product from step 3 (895 mg, 2.98 mmol) in tert-butanol (5 mL). The reaction was heated to 50° C. for 3 h, then cooled to ambient temperature and diluted with water. The pH of the solution was adjusted to neutral (pH 7) with concentrated HCl, concentrated in vacuo, extracted with CH2Cl2 and the extracts passed through a hydrophobic frit. Concentration in vacuo and purification by chromatography (0-40% EtOAc-cyclohexanes) gave the title compounds as a yellow solid (1.03 g). 1H NMR (300 MHz, CDCl3) δ d 7.53-7.42 (m, 1H), 7.16-7.13 (m, 1H), 7.03-6.94 (m, 2H), 3.64 (d, J=4.8 Hz, 1H), 2.48-2.04 (m, 2H), 1.78-1.53 (m, 2H), 1.20 (s, 3H), 1.03 (s, 3H). LCMS (m/z, Method B) ES+ 439 [M+1]+.
Step 5: Trifluoro-methanesulfonic Acid (1R,8S)-5-(2,6-difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-trien-1-yl Ester
A solution of the products from step 4 (2.93 g, 6.67 mmol) and hydrazine hydrochloride (1.14 g, 16.7 mmol) in n-butanol (20 mL) and ethylene glycol (25 mL) was stirred at 150° C. for 3 h. The reaction was cooled, concentrated and the residue partitioned between H2O-EtOAc. The organic phase was washed with brine, dried (Na2SO4), and purified by chromatography (5-40% EtOAc-cyclohexane) gave the title compound as a yellow solid (1.71 g). 1H NMR (400 MHz, DMSO-d6) d 7.85 (s, 1H), 7.66-7.57 (m, 1H), 7.30 (dd, J=8.2, 8.2 Hz, 2H), 3.26 (d, J=3.0 Hz, 1H), 2.63-2.49 (m, 2H), 2.18-2.10 (m, 1H), 1.46-1.37 (m, 1H), 1.23 (s, 3H), 0.65 (s, 3H). LCMS (m/z, Method B) ES+ 435 [M+1]+.
Step 6: (1R,8S)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2,4,6-trien-1-ol
A solution of the product from step 5 (2.55 g, 5.87 mmol) in 1M NaOH (11.7 mL) and 1,4-dioxane (20 mL) was heated at 100° C. for 1.5 h. The pH of the solution was adjusted to neutral (pH 7) with concentrated HCl, concentrated, and extracted into CH2Cl2. The organic phase was passed through a hydrophobic frit, concentrated and purified by chromatography (40-55% EtOAc-cyclohexane) to give the title compound as a white solid (1.54 g). 1H NMR (300 MHz, CDCl3): δ 7.44-7.33 (m, 2H), 7.04 (dd, J=8.0, 8.0 Hz, 2H), 3.76-3.70 (m, 1H), 2.94 (d, J=3.9 Hz, 1H), 2.37-2.28 (m, 2H), 1.65 (d, J=9.1 Hz, 1H), 1.32 (s, 1H), 1.23 (s, 3H), 0.68 (s, 3H). LCMS (m/z, Method B) ES+ 303 [M+1]+.
Step 7: (R)-2-[(1R,8S)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yloxy]-butyric Acid Methyl Ester
To a solution of the product from step 6 (3.48 g, 11.5 mmol) in dry DMF (10 mL) at RT under N2 was added NaH (60% in mineral oil, 691 mg, 17.3 mmol) and the resulting brown suspension stirred under N2 at RT for 30 minutes. Methyl 2-bromobutyrate (2.0 mL, 17 mmol) was added and the suspension stirred at RT for 1.5 h. NaH (60% in mineral oil, 461 mg, 11.5 mmol) was added and the mixture stirred at RT for 30 minutes, then methyl 2-bromobutyrate (2.0 mL, 17 mmol) was added and the red-brown suspension stirred at RT for 2 hours. The mixture was concentrated and the residue suspended in aqueous 1 N HCl solution (50 mL) and extracted with CH2Cl2 (2×50 mL). The combined organics were passed through a hydrophobic frit, concentrated and purified by chromatography (10-50% EtOAc-cyclohexane) to give the title compound as a pale yellow oil that became a pale yellow solid on standing (2.27 g). 1H NMR (300 MHz, CDCl3) δ 7.39 (tt, J=6.3, 8.5 Hz, 1H), 7.29 (t, J=1.2 Hz, 1H), 7.07-6.97 (m, 2H), 4.85 (dd, J=5.4, 6.9 Hz, 1H), 3.79 (s, 3H), 2.87 (d, J=4.3 Hz, 1H), 2.42-2.30 (m, 1H), 2.24 (dt, J=3.8, 11.3 Hz, 1H), 2.08-1.89 (m, 3H), 1.78 (ddd, J=3.6, 9.4, 11.8 Hz, 1H), 1.24 (s, 3H), 1.08 (t, J=7.4 Hz, 3H), 0.80 (s, 3H). LCMS (m/z, Method B) ES+ 403 [M+1]+.
Step 8: (R)-2-[(1R,8S)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yloxy]-butyric Acid
To a solution of the product from step 7 (1.01 g, 2.50 mmol) in MeOH (5 mL) and THF (5 mL) at RT was added a solution of NaOH (200 mg, 5.00 mmol) in water (5 mL) and the resulting solution stirred at RT for 3 days. The solution was diluted with water, washed with Et2O, then the aqueous layer acidified with conc. HCl solution and extracted with CH2Cl2. The organics were passed through a hydrophobic frit and concentrated to leave a pale yellow foam (845 mg). 1H NMR (300 MHz, CDCl3) δ 7.49-7.38 (m, 2H), 7.11-7.01 (m, 2H), 4.72 (dd, J=4.0, 7.7 Hz, 1H), 3.75 (t, J=6.7 Hz, 1H), 2.95 (d, J=4.1 Hz, 1H), 2.44-2.17 (m, 3H), 2.01-1.83 (m, 2H), 1.78-1.70 (m, 1H), 1.28 (s, 3H), 1.06 (t, J=7.5 Hz, 3H), 0.84 (s, 3H). LCMS (m/z, Method B) ES+ 389 [M+1]+.
Step 9: (R)-2-[(1R,8S)-5-(2,6-Difluoro-phenyl)-11,11-dimethyl-3,4-diaza-tricyclo[6.2.1.0*2,7*]undeca-2(7),3,5-trien-1-yloxy]-butyramide
To a yellow solution of the product from step 8 (194 mg, 0.50 mmol), aqueous NH4OH solution (28%, 46 mg, 0.75 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) was added HATU (266 mg, 0.70 mmol) and the resulting orange solution stirred at RT for 2 hours. Aqueous NH4OH solution (28%, 23 mg, 0.38 mmol) and HATU (133 mg, 0.35 mmol) were added and the mixture stirred at RT for 75 minutes. The solution was concentrated, suspended in sat. aqueous NaHCO3 (5 mL) and water (5 mL), then extracted with CH2Cl2 (2×10 mL). The combined organic extracts were passed through a hydrophobic frit, concentrated and purified by chromatography (1-6% MeOH—CH2Cl2). One third of the material was further purified by MDAP to leave a white solid (42 mg). 1H NMR (400 MHz, CDCl3) δ 7.41 (tt, J=6.4, 8.5 Hz, 1H), 7.34 (s, 1H), 7.09-7.00 (m, 2H), 6.69 (br s, 1H), 5.55 (br s, 1H), 4.95 (t, J=5.5 Hz, 1H), 2.91 (d, J=3.5 Hz, 1H), 2.41-2.20 (m, 3H), 2.16-2.04 (m, 1H), 1.82-1.74 (m, 1H), 1.40-1.29 (m, 1H), 1.25 (s, 3H), 1.10 (t, J=7.5 Hz, 3H), 0.78 (s, 3H). LCMS (m/z, Method A) ES+ 388.2 [M+1]+.
EXAMPLE 2: TERT-BUTYL 3-((5R,8S)-3-(2,6-DIFLUOROPHENYL)-9,9-DIMETHYL-6,7-DIHYDRO-5,8-METHANO CINNOLIN-8(5H)-YL)PIPERAZINE-1-CARBOXYLATE AND TERT-BUTYL 2-((5R,8S)-3-(2,6-DIFLUOROPHENYL)-9,9-DIMETHYL-6,7-DIHYDRO-5,8-METHANOCINNOLIN-8(5H)-YL)PIPERAZINE-1-CARBOXYLATE
Figure US09994551-20180612-C00020
Step 1: 2-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)-2-oxoacetaldehyde
To a solution of 1-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)ethan-1-one (6.0 g, 18.3 mmol) in 1,4-dioxane (200 mL) and H2O (8 mL) was added selenium dioxide (3.05 g, 27.4 mmol), the mixture was heated at 100° C. for 20 h. The reaction was cooled to room temperature and filtered through a pad of silica. The filtrate was evaporated under reduced pressure to give the title compound as yellow oil, which was used directly for next step without further purification (6.05 g). LCMS (ESI): m/z=343.2 [M+H]+.
Step 2: (5R,8S)-3-(2,6-Difluorophenyl)-9,9-dimethyl-8-(piperazin-2-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline
To a solution of the product from step 1 (6.05 g, 17.67 mmol) in MeOH (50 mL) was added ethane-1,2-diamine (1.2 mL, 17.67 mmol) and the reaction was stirred at room temperature for 1 h. Sodium borohydride (3.3 g, 88.3 mmol) was added and the mixture was stirred at 0° C. for 0.5 h then quenched with H2O (100 mL) and extracted with DCM (2×50 mL). The combined organic phases were dried (Na2SO4), filtered, concentrated and purified by flash chromatography (0-100% EtOAc-petroleum ether, then 0-20% MeOH-DCM (10% NH3 in MeOH) to give the first diastereoisomer (0.70 g) as a pale yellow solid and the second diastereoisomer as a yellow solid (3.51 g).
LCMS (ESI): m/z=371.1 [M+H]+.
Step 3: tert-Butyl 3-((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)piperazine-1-carboxylate and tert-butyl 2-((5R,8S)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)piperazine-1-carboxylate
To a solution of the product from step 2 (3.51 g, 9.48 mmol) and Et3N (2.6 mL, 18.69 mmol) in CH2Cl2 (50 mL) was added di-tert-butyl dicarbonate (2.07 g, 9.48 mmol). The mixture was stirred at room temperature for 1 h, quenched with water (50 mL) and extracted with DCM (2×50 mL). The combined organic phases were dried (Na2SO4), concentrated and purified by prep-HPLC (CH3CN 25-55%/0.1% NH4HCO3 solution) to afford the title compounds as a white solids (1.70 g and 0.75 g).
1H NMR (400 MHz, CD3OD-d4): δ 7.66 (s, 1H), 7.61-7.56 (m, 1H), 7.21-7.16 (m, 2H), 4.44 (d, J=9.6 Hz, 1H), 4.02 (d, J=12.8 Hz, 1H), 3.20-3.12 (m, 3H), 3.04 (d, J=4.0 Hz, 1H), 2.99-2.88 (m, 1H), 2.83-2.76 (m, 1H), 2.42-2.30 (m, 2H), 1.69-1.64 (m, 1H), 1.48 (m, 9H), 1.29 (s, 3H), 1.28-1.17 (m, 1H), 0.88 (s, 3H). LCMS (ESI): m/z=471.2 [M+H]+.
1H NMR (400 MHz, CD3OD-d4): δ 7.65 (s, 1H), 7.60-7.56 (m, 1H), 7.20-7.16 (m, 2H), 4.21 (d, J=12.0 Hz, 1H), 4.04 (d, J=10.4 Hz, 1H), 3.33-3.22 (m, 2H), 3.09-2.86 (m, 4H), 2.39-2.34 (m, 2H), 1.55-1.51 (m, 10H), 1.34-1.29 (m, 4H), 0.83 (s, 3H). LCMS (ESI): m/z=471.3 [M+H]+.
EXAMPLE 3: 5-((5R,8R)-3-(2,6-DIFLUOROPHENYL)-9,9-DIMETHYL-6,7-DIHYDRO-5,8-METHANOCINNOLIN-8(5H)-YL)PIPERIDIN-2-ONE
Figure US09994551-20180612-C00021
Step 1: ((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methyl trifluoromethanesulfonate
To a solution of ((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methanol (6.5 g, 20.5 mmol) in CH2Cl2 (250 mL) was added portions of trifluoromethane sulfonic anhydride (11.5 g, 40.7 mmol) and pyridine (5.0 g, 63.2 mmol) at room temperature. The reaction was stirred at room temperature for 3 h, quenched with H2O (80 mL), extracted with CH2Cl2 (3×80 mL), dried (Na2SO4) and purified by chromatography (0-30% EtOAc-petroleum ether) to give the title compound as a yellow solid (6 g). LCMS (ESI): m/z=449.1 [M+H]+.
Step 2: 2-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)acetonitrile
To a solution of the product from step 1 (6.0 g, 13.3 mmol) in DMF (30 mL) was added NaCN (2.0 g, 40.8 mmol), the reaction was heated at 80° C. for 12 h. The reaction was cooled to room temperature, quenched with water (50 mL), extracted with CH2Cl2 (3×80 mL), dried (Na2SO4), concentrated and purified by chromatography (0-50% EtOAc-petroleum ether) to give the title product as a yellow solid (4 g). LCMS (ESI): m/z=326.1 [M+H]+.
Step 3: 2-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methano cinnolin-8(5H)-yl)-3-oxopropanenitrile
To a solution of the product from step 2 (1.0 g, 3.07 mmol) in THF (20 mL) was added dropwise LDA (2.0 M in THF, 3.38 mL, 6.76 mmol) at −78° C., the mixture was stirred at −78° C. for 1 h then ethyl formate (671 mg, 9.07 mmol) was added. The mixture was stirred at −78° C. for 2 h, quenched with sat. aqueous NH4Cl solution (10 mL), extracted with EtOAc (2×20 mL), dried (Na2SO4) and purified by chromatography (0-10% MeOH-DCM) to give the title product as a yellow solid (600 mg). LCMS (ESI): m/z=354.1 [M+H]+.
Step 4: Ethyl (E)-4-cyano-4-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)but-2-enoate
A mixture of ethyl(triphenylphosphoranylidene)acetate (590 mg, 1.7 mmol) and the product from step 3 (500 mg, 1.41 mmol) in toluene (20 mL) was heated at 140° C. in a microwave oven for 1 hour. The mixture was concentrated and purified by chromatography (0-50% EtOAc-petroleum ether) to give the title product as brown oil (700 mg). LCMS (ESI): m/z=424.1 [M+H]+.
Step 5: 5-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methano cinnolin-8(5H)-yl)piperidin-2-one
To a solution of the product from step 4 (990 mg, 2.34 mmol) in EtOH (30 mL) was added Raney Nickel (2.0 g, 23.4 mmol). The mixture was stirred at 25° C. under hydrogen atmosphere for 16 h, then the mixture was filtered and the filtrate was concentrated to give crude product. To the crude product in EtOH (30 mL) was added AcOH (4 mL) and Raney Nickel (1.8 g, 21.1 mmol) at room temperature. The mixture was stirred at 25° C. under hydrogen atmosphere (1 atm) for 16 h, then the mixture was filtered and the filtrate was concentrated under reduced pressure and purified by Prep-HPLC to give the title product as a white solid (600 mg). 1H NMR (400 MHz, CD3OD-d4): δ 7.64 (s, 1H), 7.62-7.56 (m, 1H), 7.21-7.16 (m, 2H), 3.83-3.68 (m, 2H), 3.01 (d, J=3.2 Hz, 1H), 2.55-2.45 (m, 4H), 2.36-2.31 (m, 2H), 2.14-2.13 (m, 1H), 1.56-1.51 (m, 1H), 1.29-1.24 (m, 1H), 1.25 (s, 3H), 0.81 (s, 3H). LCMS (ESI): m/z=384.1 [M+H]+.
EXAMPLE 4: (5R,8R)-3-(2,6-DIFLUOROPHENYL)-9,9-DIMETHYL-8-((R)-PIPERIDIN-3-YL)-5,6,7,8-TETRAHYDRO-5,8-METHANOCINNOLINE
Figure US09994551-20180612-C00022
Step 1: (5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-8-((R)-piperidin-3-yl)-5,6,7,8-tetrahydro-5,8-methanocinnoline
To a solution of 5-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)piperidin-2-one (780 mg, 2.03 mmol) in THF (6 mL) was added a solution of BH3*THF complex (1 M in THF, 6.1 mL, 6.1 mmol) at room temperature. The mixture was stirred at room temperature for 4 h, quenched with MeOH (2 mL) and purified by Prep-HPLC to give the title product as a white solid (150 mg). 1H NMR (400 MHz, DMSO-d6): δ 7.62 (s, 1H), 7.62-7.58 (m, 1H), 7.31-7.27 (m, 2H), 4.12-4.11 (m, 1H), 3.44-3.41 (m, 1H), 3.17-3.16 (d, J=4 Hz, 1H), 2.92-2.87 (m, 2H), 2.78-2.73 (m, 1H), 2.22-2.08 (m, 3H), 1.68-1.65 (m, 1H), 1.47-1.42 (m, 1H), 1.28-1.24 (m, 1H), 1.13 (s, 3H), 1.09-1.03 (m, 1H), 0.66 (s, 3H). LCMS (ESI): m/z=370.1 [M+H]+.
EXAMPLE 5: (S)-2-((5R,8R)-3-(2,6-DIFLUOROPHENYL)-9,9-DIMETHYL-6,7-DIHYDRO-5,8-METHANOCINNOLIN-8(5H)-YL)-N-METHYLMORPHOLINE-4-CARBOXAMIDE
Figure US09994551-20180612-C00023
Figure US09994551-20180612-C00024
Step 1: (5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnoline-8(5H)-carbaldehyde
To a solution of ((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methanol (3.24 g, 10.24 mmol) in CH2Cl2 (100 mL) at room temperature was added Dess-Martin periodinane (8.69 g, 20.48 mmol) in portions. The reaction was stirred at room temperature for 2 h, filtered and the filtrate was concentrated. The residue was diluted with Et2O (100 mL), washed with saturated aqueous Na2S2O3 (2×50 mL), brine (50 mL), dried (Na2SO4), filtered, and then concentrated under reduced pressure to give the title product as a pale yellow solid (1.78 g). LCMS (ESI): m/z=315.1 [M+H]+.
Step 2: Ethyl (Z)-2-(((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methylene)butanoate
To a solution of ethyl 2-(diethoxyphosphoryl)butanoate (960 mg, 3.36 mmol) in dry THF (25 mL) was added NaH (152 mg, 3.81 mmol) at 0° C. under nitrogen atmosphere. The mixture was stirred at 0° C. for 1 h, then the product from step 1 (960 mg, 3.05 mmol) in THF (10 mL) was added. The reaction was heated at 80° C. for 2 h, cooled to room temperature, quenched with saturated aqueous NH4Cl (40 mL), extracted with EtOAc (2×60 mL), dried (Na2SO4), and purified by chromatography (0-25% EtOAc-petroleum ether) to afford the title compound as a yellow solid (435 mg). LCMS (ESI): m/z=413.2 [M+H]+.
Step 3: Ethyl (R)-2-(((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methyl)butanoate
To a solution of the product from step 2 (435 mg, 1.05 mmol) in MeOH (40 mL) was added 10% Pd on activated carbon power (111 mg, 0.11 mmol) and acetic acid glacial (4.0 mL). The mixture was stirred at room temperature under hydrogen atmosphere for 12 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated to dryness. The residue was purified by Chiral HPLC (OZ—H, CO2/methanol (0.1% NH4OH)=65/35) to give the first isomer as a white solid (100 mg) and a second isomer as a white solid (90 mg). LCMS (ESI): m/z=415.2 [M+H]+.
Step 4: (R)-2-(((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methyl)butanoic Acid
To a solution of the product from step 3 (100 mg, 0.24 mmol) in THF/MeOH/H2O (2:4:1, 3.5 mL) was added lithium hydroxide hydrate (100 mg, 2.38 mmol). The mixture was stirred at 40° C. for 3 days then evaporated in vacuo and the residue was diluted with H2O (15 mL), and extracted with EtOAc (2×10 mL). The aqueous layer was acidified to pH=2 with concentrated aqueous HCl and then extracted with EtOAc (2×10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (58 mg). LCMS (ESI): m/z=387.2 [M+H]+.
Step 5: (R)-2-(((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methyl)butanamide
A mixture of the product from step 4 (58 mg, 0.15 mmol), NH4Cl (80 mg, 1.5 mmol), HOBt (41 mg, 0.3 mmol), EDCI (58 mg, 0.3 mmol) and triethylamine (0.22 mL, 1.57 mmol) in DMF (3 mL) were heated at 50° C. for 4 h. The reaction was quenched with H2O (20 mL), extracted with EtOAc (2×20 mL), dried (Na2SO4) and purified by prep-HPLC (CH3CN 25-45%/0.1% NH4HCO3 in H2O) to give the title compound as a white solid (42 mg).
1H NMR (400 MHz, CD3OD-d4): δ 7.62-7.56 (m, 2H), 7.20-7.16 (m, 2H), 3.06-2.99 (m, 2H), 2.50-2.47 (m, 1H), 2.37-2.28 (m, 2H), 1.79-1.71 (m, 3H), 1.49-1.46 (m, 1H), 1.33-1.31 (m, 1H), 1.16 (s, 3H), 1.00 (t, J=6.6 Hz, 3H), 0.66 (s, 3H). LCMS (ESI): m/z=386.2 [M+H]+.
EXAMPLE 6: (S)-2-((5R,8R)-3-(2,6-DIFLUOROPHENYL)-9,9-DIMETHYL-6,7-DIHYDRO-5,8-METHANOCINNOLIN-8(5H)-YL)-N-METHYLMORPHOLINE-4-CARBOXAMIDE
Figure US09994551-20180612-C00025
Step 1 Ethyl (S)-2-(((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methyl)butanoate
To a solution of ethyl (Z)-2-(((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)methylene)butanoate (435 mg, 1.05 mmol) in MeOH (40 mL) was added 10% Pd on activated carbon power (111 mg, 0.11 mmol) and acetic acid glacial (4.0 mL). The mixture was stirred at room temperature under hydrogen atmosphere for 12 h. The reaction mixture was filtered through a pad of diatomaceous earth, concentrated and purified by chiral column HPLC (OZ—H, CO2/MeOH (0.1% NH4OH)=65/35) to give the title compound as a white solid (90 mg). LCMS (ESI): m/z=415.2 [M+H]+.
Step 2: (S)-2-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)-N-methylmorpholine-4-carboxamide
The product from step 1 (90 mg, 0.22 mmol) was reacted as described in example 4, step 4 and 5 to give the title compound as a white solid (40 mg). 1H NMR (400 MHz, CD3OD-d4): δ 7.61-7.54 (m, 2H), 7.20-7.15 (m, 2H), 3.45-3.39 (m, 1H), 3.04 (d, J=1.0 Hz, 1H), 2.34-2.27 (m, 1H), 2.23-2.11 (m, 2H), 2.03-1.99 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.53 (m, 1H), 1.32-1.24 (m, 1H), 1.11 (s, 3H), 1.07 (t, J=7.2 Hz, 3H), 0.64 (s, 3H). LCMS (ESI): m/z=386.2 [M+H]+.
EXAMPLE 7: (R)-4-BENZYL-2-((5R,8R)-3-(2,6-DIFLUOROPHENYL)-9,9-DIMETHYL-6,7-DIHYDRO-5,8-METHANOCINNOLIN-8(5H)-YL)MORPHOLINE AND (S)-4-BENZYL-2-((5R,8R)-3-(2,6-DIFLUOROPHENYL)-9,9-DIMETHYL-6,7-DIHYDRO-5,8-METHANOCINNOLIN-8(5H)-YL)MORPHOLINE
Figure US09994551-20180612-C00026
Figure US09994551-20180612-C00027
Step 1: 2-Bromo-1-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)ethan-1-one
To a solution of 1-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)ethan-1-one (8.40 g, 25.58 mmol) in THF (100 mL) was added phenyltrimethylammonium tribromide (9.62 g, 25.58 mmol), the mixture was heated at 60° C. for 16 h. The reaction was cooled to room temperature and water (80 mL) was added. The resulting mixture was extracted with EtOAc (2×120 mL), dried (Na2SO4) and concentrated to give the title compound (6.95 g) as a yellow solid. LCMS (ESI): m/z=407.1 [M+H]+.
Step 2: 2-(Benzyl(2-hydroxyethyl)amino)-1-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)ethan-1-one
To a solution of the product from step 1 (6.95 g, 17.1 mmol) in THF (150 mL) was added 2-(benzylamino)ethanol (5.68 g, 37.6 mmol). The mixture was stirred at room temperature for 2 h. The resulting reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (0-30% EtOAc-petroleum ether) to afford the title compound as a yellow solid (8.16 g). LCMS (ESI): m/z=478.3 [M+H]+.
Step 3: 2-(Benzyl(2-hydroxyethyl)amino)-1-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)ethan-1-ol
To a solution of the product from step 2 (8.16 g, 17.09 mmol) in MeOH (50 mL) was added sodium borohydride (3.06 g, 85.45 mmol) in portions at room temperature. The mixture was stirred for 1 h, quenched with water (100 mL), extracted with EtOAc (3×60 mL), dried (Na2SO4) and concentrated to give the title compound as a yellow solid (7.34 g).
LCMS (ESI): m/z=480.3 [M+H]+.
Step 4: (R)-4-Benzyl-2-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)morpholine and (S)-4-Benzyl-2-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)morpholine
A mixture of the product from step 3 (7.34 g, 15.31 mmol) and methanesulfonic acid (56 mL) was heated at 110° C. for 18 h. The resulting reaction was cooled to room temperature and poured into ice water. The mixture was neutralized (pH 7) with 2 M aqueous NaOH solution, and then extracted with EtOAc (3×100 mL), dried (Na2SO4), purified by chromatography (0-45% 5% Et3N in EtOAc-petroleum ether) to give the first isomer as a white solid (2.04 g) and the second isomer as a white solid (2.31 g).
LCMS (ESI): m/z=462.2 [M+H]+.
EXAMPLE 8: (S)-2-((5R,8R)-3-(2,6-DIFLUOROPHENYL)-9,9-DIMETHYL-6,7-DIHYDRO-5,8-METHANOCINNOLIN-8(5H)-YL)MORPHOLINE
Figure US09994551-20180612-C00028
Step 1: (S)-2-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)morpholine
To a solution of (S)-4-benzyl-2-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)morpholine (2.04 g, 4.42 mmol) in dichloromethane (80 mL) was added 1-chloroethyl carbonochloridate (1.89 g, 13.3 mmol) at room temperature. The mixture was heated at 70° C. for 3 h, and then concentrated to dryness under reduced pressure. Methanol (50 mL) was added to the residue and the mixture was refluxed for 30 min. After removal of the solvent, the residue was purified by chromatography (0-20% MeOH-EtOAc containing 5% Et3N) to afford the title compound as an off-white solid (0.94 g). 1H NMR (400 MHz, CD3OD-d4): δ 7.61 (s, 1H), 7.60-7.55 (m, 1H), 7.20-7.16 (m, 2H), 4.23 (d, J=10.8 Hz, 1H), 4.02 (d, J=12.8 Hz, 1H), 3.95 (dd, J=11.6, 2.4 Hz, 1H), 3.76-3.70 (m, 1H), 2.99-2.84 (m, 4H), 2.59-2.52 (m, 1H), 2.41-2.35 (m, 1H), 1.40-1.27 (m, 2H), 1.26 (s, 3H), 0.75 (s, 3H). LCMS (ESI): m/z=372.2 [M+H]+.
EXAMPLE 9: (S)-2-((5R,8R)-3-(2,6-DIFLUOROPHENYL)-9,9-DIMETHYL-6,7-DIHYDRO-5,8-METHANOCINNOLIN-8(5H)-YL)-N-METHYLMORPHOLINE-4-CARBOXAMIDE
Figure US09994551-20180612-C00029
Step 1: (S)-2-((5R,8R)-3-(2,6-Difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)-N-methylmorpholine-4-carboxamide
To a solution of (S)-2-((5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnolin-8(5H)-yl)morpholine (70 mg, 0.19 mmol) and Et3N (0.07 mL, 0.50 mmol) in CH2Cl2 (5 mL) was added dropwise methylcarbamic chloride (27.0 mg, 0.29 mmol) at 0° C. The mixture was stirred at room temperature for 0.5 h, quenched with water (5 mL), and extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried (Na2SO4) and purified by prep-HPLC eluting with 25-55% CH3CN/H2O (0.1% NH4HCO3 in H2O) to give the title compound as off-white solid (37 mg). 1H NMR (400 MHz, CD3OD-d4): δ 7.65 (s, 1H), 7.62-7.55 (m, 1H), 7.22-7.16 (m, 2H), 4.79 (d, J=12.8 Hz, 1H), 4.13 (dd, J=10.4, 2.0 Hz, 1H), 4.01-3.94 (m, 2H), 3.69-3.62 (m, 1H), 3.15-3.09 (m, 1H), 3.04-2.97 (m, 2H), 2.80 (s, 3H), 2.60-2.54 (m, 1H), 2.44-2.37 (m, 1H), 1.45-1.31 (m, 2H), 1.30 (s, 3H), 0.77 (s, 3H). LCMS (ESI): m/z=429.3 [M+H]+.
The above compounds, together with additional compounds made using the above procedure, are shown in Table 1 below, together with RORc IC50 (micromolar) data for selected compounds determined using the assays described below.
TABLE 1
Structure Name IC50
1
Figure US09994551-20180612-C00030
 		(S)-N-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8-yl)- 2-hydroxy-N-methylpropanamide 0.92
2
Figure US09994551-20180612-C00031
 		5-((5R,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-1,3,4- oxadiazole-2-carboxamide 0.52
3
Figure US09994551-20180612-C00032
 		5-((5R,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-N-methyl- 1,3,4-oxadiazole-2-carboxamide 0.283
4
Figure US09994551-20180612-C00033
 		(R)-2-(((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)methyl)butanamide 0.0824
5
Figure US09994551-20180612-C00034
 		(S)-2-(((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)methyl)butanamide 0.0674
6
Figure US09994551-20180612-C00035
 		(5S,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl trifluoromethanesulfonate 0.006
7
Figure US09994551-20180612-C00036
 		(5S,8R)-3-(2,6-difluorophenyl)-8- ethoxy-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnoline 0.0093
8
Figure US09994551-20180612-C00037
 		2-((((5S,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)oxy)methyl)-5- methyl-1,3,4-oxadiazole 0.14
9
Figure US09994551-20180612-C00038
 		5-(((5S,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)oxy)-N- methylpyrazine-2-carboxamide 0.325
10
Figure US09994551-20180612-C00039
 		(5S,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl azetidine-1- carboxylate 0.353
11
Figure US09994551-20180612-C00040
 		(5S,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-8-(pyrazin-2-yloxy)-5,6,7,8- tetrahydro-5,8-methanocinnoline 0.0799
12
Figure US09994551-20180612-C00041
 		(5S,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-8-(pyridin-2-yloxy)-5,6,7,8- tetrahydro-5,8-methanocinnoline 0.0425
13
Figure US09994551-20180612-C00042
 		(5S,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-8-(pyrimidin-2-ylmethoxy)- 5,6,7,8-tetrahydro-5,8- methanocinnoline 0.515
14
Figure US09994551-20180612-C00043
 		(5S,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-8-(pyrimidin-2-yloxy)- 5,6,7,8-tetrahydro-5,8- methanocinnoline 0.084
15
Figure US09994551-20180612-C00044
 		3-(((5S,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)oxy)-N- methylpyrazine-2-carboxamide 0.0722
16
Figure US09994551-20180612-C00045
 		(5S,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-8-(pyridazin-3-yloxy)- 5,6,7,8-tetrahydro-5,8- methanocinnoline 0.254
17
Figure US09994551-20180612-C00046
 		(5S,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-8-(pyrazin-2-ylmethoxy)- 5,6,7,8-tetrahydro-5,8- methanocinnoline 0.133
18
Figure US09994551-20180612-C00047
 		3-(((5S,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)oxy)-N-(2- hydroxyethyl)pyrazine-2-carboxamide 0.34
19
Figure US09994551-20180612-C00048
 		(S)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-ethylbutanamide 0.0347
20
Figure US09994551-20180612-C00049
 		2-((R)-1-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)propyl)-5-methyl-1,3,4- oxadiazole 0.0241
21
Figure US09994551-20180612-C00050
 		2-((S)-1-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)propyl)-5-methyl-1,3,4- oxadiazole 0.051
22
Figure US09994551-20180612-C00051
 		(R)-2 -(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-ethylbutanamide 1.01
23
Figure US09994551-20180612-C00052
 		(S)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-(2- hydroxyethyl)butanamide 0.0445
24
Figure US09994551-20180612-C00053
 		(5S,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-8-phenoxy-5,6,7,8- tetrahydro-5,8-methanocinnoline 0.0144
25
Figure US09994551-20180612-C00054
 		(5S,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-8-((2-methylpyridin-4- yl)oxy)-5,6,7,8-tetrahydro-5,8- methanocinnoline 0.844
26
Figure US09994551-20180612-C00055
 		(S)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-(2- (methylsulfonyl)ethyl)butanamide 0.0427
27
Figure US09994551-20180612-C00056
 		(5S,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-8-(pyridin-3-yloxy)-5,6,7,8- tetrahydro-5,8-methanocinnoline 0.067
28
Figure US09994551-20180612-C00057
 		(5S,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-8-(pyrimidin-5-yloxy)- 5,6,7,8-tetrahydro-5,8- methanocinnoline 0.185
29
Figure US09994551-20180612-C00058
 		6-(((5S,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)oxy)-N- methylpyrazine-2-carboxamide 0.385
30
Figure US09994551-20180612-C00059
 		6-(((5S,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)oxy)-N-(2- hydroxyethyl)pyrazine-2-carboxamide 0.836
31
Figure US09994551-20180612-C00060
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)butanamide 0.0088
32
Figure US09994551-20180612-C00061
 		(5-((R)-1-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)propyl)-1,3,4-oxadiazol-2- yl)methanol 0.0057
33
Figure US09994551-20180612-C00062
 		5-(((5S,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)oxy)pyridin- 2(1H)-one 0.12
34
Figure US09994551-20180612-C00063
 		4-(((5S,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)oxy)pyridin- 2(1H)-one 0.202
35
Figure US09994551-20180612-C00064
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)butan-1-ol 0.0198
36
Figure US09994551-20180612-C00065
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N,N-dimethylbutanamide 0.0543
37
Figure US09994551-20180612-C00066
 		1-((R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)butanoyl)azetidine-3- carbonitrile 0.0689
38
Figure US09994551-20180612-C00067
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-1-(3-(hydroxymethyl)azetidin- 1-yl)butan-1-one 0.144
39
Figure US09994551-20180612-C00068
 		(3-((R)-1-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)propyl)-1H-1,2,4-triazol-5- yl)methanol 0.827
40
Figure US09994551-20180612-C00069
 		(5S,8R)-8-((R)-1-(1H-1,2,4-triazol-3- yl)propoxy)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnoline 0.0501
41
Figure US09994551-20180612-C00070
 		5-((R)-1-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)propyl)-3-(methoxymethyl)- 1,2,4-oxadiazole 0.0040
42
Figure US09994551-20180612-C00071
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)propanamide 0.0144
43
Figure US09994551-20180612-C00072
 		(S)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)propanamide 0.30
44
Figure US09994551-20180612-C00073
 		(R)-2-cyclopropyl-2-(((5-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)acetamide 0.0145
45
Figure US09994551-20180612-C00074
 		(S)-2-cyclopropyl-2-(((5-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)acetamide 0.132
46
Figure US09994551-20180612-C00075
 		2-(1-(((5S,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8- yl)oxy)cyclopropyl)acetamide 0.0748
47
Figure US09994551-20180612-C00076
 		2-(((5S,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)oxy)acetamide 0.118
48
Figure US09994551-20180612-C00077
 		2-(((5S,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)oxy)-N-(2- hydroxy-2-methylpropyl)acetamide 0.0952
49
Figure US09994551-20180612-C00078
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)pentanamide 0.0154
50
Figure US09994551-20180612-C00079
 		(S)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)pentanamide 0.20
51
Figure US09994551-20180612-C00080
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-((S)-2- hydroxypropyl)butanamide 0.0615
52
Figure US09994551-20180612-C00081
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-(2-hydroxy-2- methylpropyl)butanamide 0.0495
53
Figure US09994551-20180612-C00082
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-(1,3-dihydroxypropan-2- yl)butanamide 0.116
54
Figure US09994551-20180612-C00083
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-((R)-2,3- dihydroxypropyl)butanamide 0.0754
55
Figure US09994551-20180612-C00084
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-(5-methyl-1,3,4-oxadiazol- 2-yl)butanamide 0.0948
56
Figure US09994551-20180612-C00085
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-((5-oxo-4,5-dihydro-1H- 1,2,4-triazol-3-yl)methyl)butanamide 0.0952
57
Figure US09994551-20180612-C00086
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-((3-hydroxyoxetan-3- yl)methyl)butanamide 0.0445
58
Figure US09994551-20180612-C00087
 		(R)-N′-acetyl-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)butanehydrazide 0.105
59
Figure US09994551-20180612-C00088
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-((5-methyl-1,3,4-oxadiazol- 2-yl)methyl)butanamide 0.0453
60
Figure US09994551-20180612-C00089
 		(R)-4-benzyl-2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholine 0.317
61
Figure US09994551-20180612-C00090
 		(S)-4-benzyl-2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholine 0.172
62
Figure US09994551-20180612-C00091
 		(R)-tert-butyl 3-((5R,8S)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)piperazine-1-carboxylate 0.136
63
Figure US09994551-20180612-C00092
 		(S)-tert-butyl 3-((5R,8S)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)piperazine-1-carboxylate 0.277
64
Figure US09994551-20180612-C00093
 		1-((R)-2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholino)ethanone 0.308
65
Figure US09994551-20180612-C00094
 		(R)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-4- (methylsulfonyl)morpholine 0.224
66
Figure US09994551-20180612-C00095
 		(R)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)morpholine 0.458
67
Figure US09994551-20180612-C00096
 		(R)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-4- methylmorpholine 0.215
68
Figure US09994551-20180612-C00097
 		(R)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)morpholine-4- carboxamide 0.0568
69
Figure US09994551-20180612-C00098
 		(R)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-N- methylmorpholine-4-carboxamide 0.0377
70
Figure US09994551-20180612-C00099
 		(S)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)morpholine 0.367
71
Figure US09994551-20180612-C00100
 		(S)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- thanocinnolin-8-yl)-4- methylmorpholine 0.375
72
Figure US09994551-20180612-C00101
 		1-((S)-2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholino)ethanone 0.119
73
Figure US09994551-20180612-C00102
 		(S)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-4- (methylsulfonyl)morpholine 1.03
74
Figure US09994551-20180612-C00103
 		(S)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-N- methylmorpholine-4-carboxamide 0.024
75
Figure US09994551-20180612-C00104
 		1-((R)-2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholino)-2-hydroxyethanone 0.234
76
Figure US09994551-20180612-C00105
 		1-((S)-2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholino)-2,3-dihydroxypropan- 1-one 0.277
77
Figure US09994551-20180612-C00106
 		1-((S)-2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholino)-2,3-dihydroxypropan- 1-one 0.194
78
Figure US09994551-20180612-C00107
 		1-((R)-2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholino)-2,3-dihydroxypropan- 1-one 0.213
79
Figure US09994551-20180612-C00108
 		(R)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-4-(pyridin-2- yl)morpholine 0.412
80
Figure US09994551-20180612-C00109
 		(S)-4-(2,2-difluoroethyl)-2-((5R,8R)-3- (2,6-difluorophenyl)-9,9-dimethyl- 5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)morpholine 0.674
81
Figure US09994551-20180612-C00110
 		(S)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)morpholine-4- carboxamide 0.0662
82
Figure US09994551-20180612-C00111
 		(S)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-4-(pyridin-2- yl)morpholine 0.0167
83
Figure US09994551-20180612-C00112
 		(R)-4-(2,2-difluoroethyl)-2-((5R,8R)- 3-(2,6-difluorophenyl)-9,9-dimethyl- 5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)morpholine 0.356
84
Figure US09994551-20180612-C00113
 		(R)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-4-(3-methyl- 1,2,4-oxadiazol-5-yl)morpholine 0.277
85
Figure US09994551-20180612-C00114
 		(R)-methyl 2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholine-4-carboxylate 0.0698
86
Figure US09994551-20180612-C00115
 		(R)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-N,N- dimethylmorpholine-4-carboxamide 0.473
87
Figure US09994551-20180612-C00116
 		(S)-methyl 2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholine-4-carboxylate 0.0368
88
Figure US09994551-20180612-C00117
 		(R)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-N,N- dimethylmorpholine-4-carboxamide 0.369
89
Figure US09994551-20180612-C00118
 		6-((R)-2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholine-4-carbonyl)pyridazin- 3(2H)-one 0.237
90
Figure US09994551-20180612-C00119
 		((R)-2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholino)(oxazol-5-yl)methanone 0.0745
91
Figure US09994551-20180612-C00120
 		(S)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-4-(3-methyl- 1,2,4-oxadiazol-5-yl)morpholine 0.101
92
Figure US09994551-20180612-C00121
 		(R)-5-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)piperidin-2-one 0.215
93
Figure US09994551-20180612-C00122
 		(S)-2-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-4-(3-methyl- 1H-1,2,4-triazol-5-yl)morpholine 0.191
94
Figure US09994551-20180612-C00123
 		((S)-2-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)morpholino)(oxazol-5-yl)methanone 0.0763
95
Figure US09994551-20180612-C00124
 		(5R,8R)-3-(2,6-difluorophenyl)-9,9- dimethyl-8-((R)-1- (methylsulfonyl)piperidin-3-yl)- 5,6,7,8-tetrahydro-5,8- methanocinnoline 0.344
96
Figure US09994551-20180612-C00125
 		(R)-3-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-N- methylpiperidine-1-carboxamide 0.013
97
Figure US09994551-20180612-C00126
 		(R)-3-((5R,8R)-3-(2,6-difluorophenyl)- 9,9-dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnolin-8-yl)-N,N- dimethylpiperidine-1-carboxamide 0.0985
98
Figure US09994551-20180612-C00127
 		1-((R)-3-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)piperidin-1-yl)ethanone 0.139
99
Figure US09994551-20180612-C00128
 		(R)-methyl 3-((5R,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)piperidine-1-carboxylate 0.0069
100
Figure US09994551-20180612-C00129
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-(2-methoxyethyl)-N- methylbutanamide 0.0464
101
Figure US09994551-20180612-C00130
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-1-(1,4-oxazepan-4-yl)butan-1- one 0.148
102
Figure US09994551-20180612-C00131
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-(2- (methylsulfonyl)ethyl)butanamide 0.0615
103
Figure US09994551-20180612-C00132
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-1-(4- (methylsulfonyl)piperazin-1-yl)butan- 1-one 0.174
104
Figure US09994551-20180612-C00133
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-(2-(dimethylamino)-2- oxoethyl)butanamide 0.0829
105
Figure US09994551-20180612-C00134
 		(R)-2-(((5S,8R)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)oxy)-N-(3- hydroxypropyl)butanamide 0.0339
106
Figure US09994551-20180612-C00135
 		(5R,8S)-3-(2,6-difluorophenyl)-8- (imidazo[1,2-a]pyrimidin-7-yl)-9,9- dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnoline 0.102
107
Figure US09994551-20180612-C00136
 		(5R,8S)-3-(2,6-difluorophenyl)-8- (imidazo[1,2-a]pyridin-5-yl)-9,9- dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnoline 0.0918
108
Figure US09994551-20180612-C00137
 		ethyl 5-((5R,8S)-3-(2,6- difluorophenyl)-9,9-dimethyl-5,6,7,8- tetrahydro-5,8-methanocinnolin-8- yl)imidazo[1,2-a]pyridine-2- carboxylate 0.096
109
Figure US09994551-20180612-C00138
 		(5R,8S)-3-(2,6-difluorophenyl)-8- (imidazo[1,2-a]pyrazin-5-yl)-9,9- dimethyl-5,6,7,8-tetrahydro-5,8- methanocinnoline 0.175
110
Figure US09994551-20180612-C00139
 		methyl (2S)-2-[[(1R,8S)-5-(2,6- difluorophenyl)-11,11-dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]oxy]butanoate 0.10
111
Figure US09994551-20180612-C00140
 		(2R)-2-[[(1R,8S)-5-(2,6- difluorophenyl)-11,11-dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]oxy]butanoic acid 0.014
112
Figure US09994551-20180612-C00141
 		methyl (2R)-2-[[(1R,8S)-5-(2,6- difluorophenyl)-11,11-dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]oxy]butanoate 0.012
113
Figure US09994551-20180612-C00142
 		(2R)-2-[[(1S,8R)-5-(2,6- difluorophenyl)-11,11-dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]oxy]butanoic acid 0.047
114
Figure US09994551-20180612-C00143
 		tert-butyl 3-[5-(2,6-difluorophenyl)- 11,11-dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]piperazine-1-carboxylate 0.42
115
Figure US09994551-20180612-C00144
 		tert-butyl 2-[5-(2,6-difluorophenyl)- 11,11-dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]piperazine-1-carboxylate 0.0031
116
Figure US09994551-20180612-C00145
 		5-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]piperidin-2-one 0.074
117
Figure US09994551-20180612-C00146
 		[2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]morpholin-4-yl]-(3-methyl- 1H-1,2,4-triazol-5-yl)methanone 0.013
118
Figure US09994551-20180612-C00147
 		5-[2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]morpholine-4-carbonyl]-1H- pyrazin-2-one 0.011
119
Figure US09994551-20180612-C00148
 		5-[2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]morpholine-4-carbonyl]-1H- pyrazin-2-one 0.021
120
Figure US09994551-20180612-C00149
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]piperidine-1-carboxamide 0.0049
121
Figure US09994551-20180612-C00150
 		5-[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]piperidine-1-carbonyl]-1H- pyrazin-2-one 0.011
122
Figure US09994551-20180612-C00151
 		[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-oxazol-4-yl- methanone 0.021
123
Figure US09994551-20180612-C00152
 		3-[2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]morpholine-4-carbonyl]-1H- pyridazin-6-one 0.72
124
Figure US09994551-20180612-C00153
 		(6-chloropyridazin-3-yl)-[2-[5-(2,6- difluorophenyl)-11,11-dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]morpholin-4-yl]methanone 0.14
125
Figure US09994551-20180612-C00154
 		3-[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]piperidine-1-carbonyl]-1H- pyridazin-6-one 0.074
126
Figure US09994551-20180612-C00155
 		ethyl 2-[2[5-(2,6-difluorophenyl)- 11,11-dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]morpholin-4-yl]oxazole-4- carboxylate 0.43
127
Figure US09994551-20180612-C00156
 		ethyl 2-[2-[5-(2,6-difluorophenyl)- 11,11-dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]morpholin-4-yl]oxazole-4- carboxylate 0.0050
128
Figure US09994551-20180612-C00157
 		[2-[2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]morpholin-4-yl]oxazol-4- yl]methanol 0.037
129
Figure US09994551-20180612-C00158
 		[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-(3-methyl-1H- 1,2,4-triazol-5-yl)methanone 0.083
130
Figure US09994551-20180612-C00159
 		[2-[2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]morpholin-4-yl]oxazol-4- yl]methanol 0.0088
131
Figure US09994551-20180612-C00160
 		[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-isoxazol-3-yl- methanone 0.0062
132
Figure US09994551-20180612-C00161
 		[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-pyrazin-2-yl- methanone 0.014
133
Figure US09994551-20180612-C00162
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]piperidin-2-one 0.00062
134
Figure US09994551-20180612-C00163
 		2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-4-(4-methyloxazol-2- yl)morpholine 0.0040
135
Figure US09994551-20180612-C00164
 		[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-(1H-pyrazol-3- yl)methanone 0.0067
136
Figure US09994551-20180612-C00165
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-ethyl-piperidine-1- carboxamide 0.029
137
Figure US09994551-20180612-C00166
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-isopropyl-piperidine-1- carboxamide 0.042
138
Figure US09994551-20180612-C00167
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-methyl-piperidine-1- sulfonamide 0.012
139
Figure US09994551-20180612-C00168
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]piperidin-2-one 4.4
140
Figure US09994551-20180612-C00169
 		[2-[2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]morpholin-4-yl]-4,5- dihydrooxazol-4-yl]methanol 0.0076
141
Figure US09994551-20180612-C00170
 		2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-(2-hydroxy-1-methyl- ethyl)morpholine-4-carboxamide 0.0095
142
Figure US09994551-20180612-C00171
 		2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-4-(3-methyl-1H-1,2,4- triazol-5-yl)morpholine 0.019
143
Figure US09994551-20180612-C00172
 		4-(2-benzyl-5-methyl-1,2,4-triazol-3- yl)-2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]morpholine 0.0056
144
Figure US09994551-20180612-C00173
 		2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-4-(1H-1,2,4-triazol-5- yl)morpholine 0.034
145
Figure US09994551-20180612-C00174
 		2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-4-(4-methyloxazol-2- yl)morpholine 0.018
146
Figure US09994551-20180612-C00175
 		4-(2-benzyl-5-methyl-1,2,4-triazol-3- yl)-2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]morpholine 0.037
147
Figure US09994551-20180612-C00176
 		2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-4-(3-methyl-1H-1,2,4- triazol-5-yl)morpholine 0.016
148
Figure US09994551-20180612-C00177
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-(3- hydroxycyclobutyl)piperidine-1- carboxamide 0.37
149
Figure US09994551-20180612-C00178
 		N-cyclobutyl-3-[5-(2,6- difluorophenyl)-11,11-dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]piperidine-1-carboxamide 0.0082
150
Figure US09994551-20180612-C00179
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-(2-hydroxy-2-methyl- propyl)piperidine-1-carboxamide 0.0079
151
Figure US09994551-20180612-C00180
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-(2- hydroxypropyl)piperidine-1- carboxamide 0.0077
152
Figure US09994551-20180612-C00181
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-(2- hydroxyethyl)piperidine-1- carboxamide 0.0074
153
Figure US09994551-20180612-C00182
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-[(3-hydroxyoxetan-3- yl)methyl]piperidine-1-carboxamide 0.11
154
Figure US09994551-20180612-C00183
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-(2- hydroxypropyl)piperidine-1- carboxamide 0.015
155
Figure US09994551-20180612-C00184
 		2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-4-(1H-1,2,4-triazol-5- yl)morpholine 0.060
156
Figure US09994551-20180612-C00185
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-[1- (hydroxymethyl)cyclopropyl]piperidine- 1-carboxamide 0.016
157
Figure US09994551-20180612-C00186
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-(oxetan-3-yl)piperidine- 1-carboxamide 0.0061
158
Figure US09994551-20180612-C00187
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-(2- methylsulfonylethyl)piperidine-1- carboxamide 0.013
159
Figure US09994551-20180612-C00188
 		[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-oxazol-2-yl- methanone 0.0045
160
Figure US09994551-20180612-C00189
 		[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-isoxazol-4-yl- methanone 0.20
161
Figure US09994551-20180612-C00190
 		[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-oxazol-5-yl- methanone 0.0091
162
Figure US09994551-20180612-C00191
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-(2-pyridyl)piperidine-1- carboxamide 0.075
163
Figure US09994551-20180612-C00192
 		5-(2,6-difluorophenyl)-11,11- dimethyl-1-[1-(2-pyridyl)-3-piperidyl]- 3,4-diazatricyclo[6.2.1.02,7]undeca- 2,4,6-triene 0.027
164
Figure US09994551-20180612-C00193
 		5-(2,6-difluorophenyl)-11,11- dimethyl-1-(1-pyrimidin-4-yl-3- piperidyl)-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- triene 0.020
165
Figure US09994551-20180612-C00194
 		5-(2,6-difluorophenyl)-11,11- dimethyl-1-(1-pyrazin-2-yl-3- piperidyl)-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- triene 0.024
166
Figure US09994551-20180612-C00195
 		[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-isoxazol-5-yl- methanone 0.033
167
Figure US09994551-20180612-C00196
 		[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-(1H-pyrazol-4- yl)methanone 0.0083
168
Figure US09994551-20180612-C00197
 		[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-pyridazin-3-yl- methanone 0.0071
169
Figure US09994551-20180612-C00198
 		5-(2,6-difluorophenyl)-11,11- dimethyl-1-(1-pyridazin-3-yl-3- piperidyl)-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- triene 0.040
170
Figure US09994551-20180612-C00199
 		1-[1-(6-chloropyridazin-3-yl)-3- piperidyl]-5-(2,6-difluorophenyl)- 11,11-dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- triene 0.018
171
Figure US09994551-20180612-C00200
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-[3- (hydroxymethypoxetan-3- yl]piperidine-1-carboxamide 0.0065
172
Figure US09994551-20180612-C00201
 		4-[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-1H-pyridin-2- one 0.020
173
Figure US09994551-20180612-C00202
 		5-(2,6-difluorophenyl)-11,11- dimethyl-1-[1-(3-methyl-1H-1,2,4- triazol-5-yl)-3-piperidyl]-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- triene 0.0028
174
Figure US09994551-20180612-C00203
 		6-[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-1H-pyridin-2- one 0.036
185
Figure US09994551-20180612-C00204
 		3-[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-1-piperidyl]-1H-pyridin-2- one 0.060
186
Figure US09994551-20180612-C00205
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N,4-dimethyl-piperazine-1- carboxamide 0.048
177
Figure US09994551-20180612-C00206
 		1-[3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-4-methyl-piperazin-1- yl]ethanone 0.015
178
Figure US09994551-20180612-C00207
 		5-(2,6-difluorophenyl)-11,11- dimethyl-1-(1-methylpiperazin-2-yl)- 3,4-diazatricyclo[6.2.1.02,7]undeca- 2,4,6-triene 0.013
179
Figure US09994551-20180612-C00208
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-4-methyl-piperazine-1- carboxamide 0.0029
180
Figure US09994551-20180612-C00209
 		5-(2,6-difluorophenyl)-1-(1,4- dimethylpiperazin-2-yl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- triene 0.016
181
Figure US09994551-20180612-C00210
 		2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-4-methyl-piperazine-1- carboxamide 0.062
182
Figure US09994551-20180612-C00211
 		1-[2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-4-methyl-piperazin-1- yl]ethanone 0.0091
183
Figure US09994551-20180612-C00212
 		5-(2,6-difluorophenyl)-11,11- dimethyl-1-(4-methylpiperazin-2-yl)- 3,4-diazatricyclo[6.2.1.02,7]undeca- 2,4,6-triene 0.013
184
Figure US09994551-20180612-C00213
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]piperazine-1-carboxamide 0.029
185
Figure US09994551-20180612-C00214
 		3-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N-methyl-piperazine-1- carboxamide 0.0034
186
Figure US09994551-20180612-C00215
 		2-[5-(2,6-difluorophenyl)-11,11- dimethyl-3,4- diazatricyclo[6.2.1.02,7]undeca-2,4,6- trien-1-yl]-N,4-dimethyl-piperazine-1- carboxamide 0.032
Proton NMR data for selected compounds is shown below, with the compound numbers below corresponding to the numbering in Table 1:
  • Compound 4:_1H NMR (400 MHz, CD3OD-d4): δ 7.62-7.56 (m, 2H), 7.20-7.16 (m, 2H), 3.06-2.99 (m, 2H), 2.50-2.47 (m, 1H), 2.37-2.28 (m, 2H), 1.79-1.71 (m, 3H), 1.49-1.46 (m, 1H), 1.33-1.31 (m, 1H), 1.16 (s, 3H), 1.00 (t, J=6.6 Hz, 3H), 0.66 (s, 3H).
  • Compound 5:_1H NMR (400 MHz, CD3OD-d4): δ 7.61-7.54 (m, 2H), 7.20-7.15 (m, 2H), 3.45-3.39 (m, 1H), 3.04 (d, J=1.0 Hz, 1H), 2.34-2.27 (m, 1H), 2.23-2.11 (m, 2H), 2.03-1.99 (m, 1H), 1.78-1.70 (m, 2H), 1.60-1.53 (m, 1H), 1.32-1.24 (m, 1H), 1.11 (s, 3H), 1.07 (t, J=7.2 Hz, 3H), 0.64 (s, 3H).
  • Compound 6: 1H NMR (400 MHz, DMSO) δ 7.85 (s, 1H), 7.66-7.57 (m, 1H), 7.30 (dd, J=8.2, 8.2 Hz, 2H), 3.26 (d, J=3.0 Hz, 1H), 2.63-2.49 (m, 2H), 2.18-2.10 (m, 1H), 1.46-1.37 (m, 1H), 1.23 (s, 3H), 0.65 (s, 3H).
  • Compound 7: 1H NMR (400 MHz, CDCl3) δ 7.42-7.34 (m, 1H), 7.29 (s, 1H), 7.02 (dd, J=8.0, 8.0 Hz, 2H), 4.60 (ddd, J=7.0, 8.8, 14.1 Hz, 1H), 3.99 (ddd, J=7.0, 8.8, 14.0 Hz, 1H), 2.84 (d, J=4.3 Hz, 1H), 2.38-2.28 (m, 1H), 2.24-2.16 (m, 1H), 1.84-1.77 (m, 1H), 1.36 (dd, J=7.0, 7.0 Hz, 3H), 1.33-1.23 (m, 1H), 1.16 (s, 3H), 0.73 (s, 3H).
  • Compound 12: 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J=1.6, 4.9 Hz, 1H), 7.63-7.58 (m, 1H), 7.39-7.33 (m, 2H), 7.10 (d, J=8.4 Hz, 1H), 7.03-6.90 (m, 3H), 2.94 (d, J=4.2 Hz, 1H), 2.78-2.70 (m, 1H), 2.46-2.32 (m, 2H), 1.53-1.46 (m, 1H), 1.29 (s, 3H), 0.82 (s, 3H).
  • Compound 15: 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 2H), 7.79 (d, J=3.2 Hz, 1H), 7.38-7.35 (m, 2H), 7.01 (dd, J=8.1, 8.1 Hz, 2H), 3.02 (d, J=4.9 Hz, 3H), 2.99 (d, J=4.1 Hz, 1H), 2.82-2.74 (m, 1H), 2.60-2.47 (m, 2H), 1.57-1.49 (m, 1H), 1.39 (s, 3H), 0.88 (s, 3H).
  • Compound 16: 1H NMR (400 MHz, CDCl3) δ 8.89 (dd, J=1.3, 4.4 Hz, 1H), 7.44-7.31 (m, 4H), 7.00 (dd, J=8.0, 8.0 Hz, 2H), 2.97 (d, J=4.3 Hz, 1H), 2.91-2.83 (m, 1H), 2.61-2.41 (m, 2H), 1.56 (s, 1H), 1.33 (s, 3H), 0.84 (s, 3H).
  • Compound 18: 1H NMR (400 MHz, CDCl3) δ 8.37-8.23 (m, 3H), 7.42-7.36 (m, 2H), 7.02 (dd, J=8.0, 8.0 Hz, 2H), 3.84 (q, J=4.8 Hz, 2H), 3.69-3.63 (m, 2H), 3.02-2.94 (m, 2H), 2.76-2.45 (m, 3H), 1.55-1.48 (m, 1H), 1.40 (s, 3H), 0.87 (s, 3H).
  • Compound 31: 1H NMR (CDCl3, 400 MHz): δ 7.45-7.36 (m, 1H), 7.34 (s, 1H), 7.09-7.00 (m, 2H), 6.67 (br. s, 1H), 5.57 (br. s, 1H), 4.95 (t, J=5.4 Hz, 1H), 2.91 (d, J=3.6 Hz, 1H), 2.40-2.30 (m, 2H), 2.30-2.19 (m, 1H), 2.16-2.03 (m, 1H), 1.80-1.72 (m, 1H), 1.38-1.30 (m, 1H), 1.24 (s, 3H), 1.09 (t, J=7.5 Hz, 3H), 0.78 (s, 3H).
  • Compound 35: 1H NMR (CDCl3, 400 MHz): δ 7.46-7.38 (m, 1H), 7.37 (s, 1H), 7.09-7.00 (m, 2H), 4.80 (d, J=5.5 Hz, 1H), 4.24-4.14 (m, 1H), 3.87-3.79 (m, 1H), 3.75-3.65 (m, 1H), 2.91-2.87 (m, 1H), 2.39-2.27 (m, 2H), 1.94-1.80 (m, 1H), 1.80-1.66 (m, 2H), 1.28-1.20 (ob. m, 1H), 1.25 (s, 3H), 0.96 (t, J=7.5 Hz, 3H), 0.84 (s, 3H).
  • Compound 39: 1H NMR (CDCl3, 400 MHz): δ 7.48-7.36 (m, 1H), 7.39 (s, 1H), 7.11-7.02 (m, 2H), 5.66 (br. s, 1H), 4.84 (s, 2H), 2.88 (d, J=4.3 Hz, 1H), 2.34-2.11 (m, 4H), 2.11-1.95 (m, 1H), 1.52-1.40 (m, 1H), 1.27-1.18 (ob. m, 1H), 1.21 (s, 3H), 1.00 (t, J=7.4 Hz, 3H), 0.79 (s, 3H). NH not observed.
  • Compound 42: 1H NMR (CDCl3, 400 MHz): δ 7.47-7.39 (m, 1H), 7.40 (s, 1H), 7.09-7.01 (m, 2H), 6.86 (br. s, 1H), 5.71 (br. s, 1H), 4.93 (q, J=6.7 Hz, 1H), 2.94 (d, J=4.1 Hz, 1H), 2.43-2.28 (m, 2H), 1.84-1.76 (m, 1H), 1.75 (d, J=6.8 Hz, 3H), 1.41-1.33 (m, 1H), 1.25 (s, 3H), 0.78 (s, 3H).
  • Compound 54: 1H NMR (CDCl3, 400 MHz): δ 7.45-7.38 (m, 2H), 7.38 (s, 1H), 7.09-7.00 (m, 2H), 4.73 (t, J=4.7 Hz, 1H), 4.00-3.92 (m, 1H), 3.72-3.63 (m, 2H), 3.59 (dd, J=11.4, 5.3 Hz, 1H), 3.37-3.28 (m, 1H), 2.92 (d, J=3.6 Hz, 1H), 2.38-2.31 (m, 1H), 2.12-2.02 (m, 3H), 1.76-1.69 (m, 1H), 1.33-1.25 (ob. m, 1H), 1.26 (s, 3H), 1.04 (t, J=7.4 Hz, 3H), 0.83 (s, 3H).
  • Compound 57: 1H NMR (CDCl3, 400 MHz): δ 7.51-7.44 (m, 1H), 7.44-7.37 (m, 1H), 7.36 (s, 1H), 7.08-7.00 (m, 2H), 5.04 (br. s, 1H), 4.81 (t, J=5.1 Hz, 1H), 4.69 (d, J=6.6 Hz, 1H), 4.65 (d, J=6.6 Hz, 1H), 4.54 (d, J=6.6 Hz, 1H), 4.46 (d, J=6.6 Hz, 1H), 3.97 (dd, J=13.9, 6.8 Hz, 1H), 3.69 (dd, J=14.1, 5.3 Hz, 1H), 2.92 (d, J=4.2 Hz, 1H), 2.40-2.30 (m, 1H), 2.30-2.21 (m, 1H), 2.19-2.02 (m, 2H), 1.75-1.67 (m, 1H), 1.35-1.26 (m, 1H), 1.25 (s, 3H), 1.03 (t, J=7.5 Hz, 3H), 0.82 (s, 3H).
  • Compound 59: 1H NMR (CDCl3, 400 MHz): δ 7.45-7.34 (m, 2H), 7.33 (m, 1H), 7.08-6.99 (m, 2H), 5.03 (d, J=5.4 Hz, 1H), 4.87 (dd, J=16.8, 6.5 Hz, 1H), 4.64 (dd, J=16.8, 5.1 Hz, 1H), 2.91 (d, J=3.8 Hz, 1H), 2.53 (s, 3H), 2.42-2.32 (m, 2H), 2.32-2.21 (m, 1H), 2.18-2.05 (m, 1H), 1.76-1.68 (m, 1H), 1.38-1.23 (ob. m, 1H), 1.27 (s, 3H), 1.06 (t, J=7.5 Hz, 3H), 0.79 (s, 3H).
  • Compound 60: 1H NMR (400 MHz, CDCl3): □□7.43-7.23 (m, 7H), 7.07-6.99 (m, 2H), 4.10 (dd, J=2.1, 10.6 Hz, 1H), 3.93 (ddd, J=1.3, 3.1, 11.3 Hz, 1H), 3.71 (dt, J=2.4, 11.4 Hz, 1H), 3.68 (d, J=12.8 Hz, 1H), 3.53 (d, J=13.1 Hz, 1H), 3.46 (t, J=10.9 Hz, 1H), 2.88 (td, J=1.8, 11.0 Hz, 1H), 2.85 (d, J=4.1 Hz, 1H), 2.68 (d, J=11.4 Hz, 1H), 2.42 (dt, J=3.2, 11.5 Hz, 1H), 2.24-2.16 (m, 1H), 2.09 (ddd, J=3.4, 10.6, 12.4 Hz, 1H), 1.31 (ddd, J=3.6, 9.2, 12.6 Hz, 1H), 1.20-1.11 (m, 4H), 0.88 (s, 3H).
  • Compound 61: 1H NMR (400 MHz, CDCl3): □ 7.43-7.21 (m, 7H), 7.08-7.00 (m, 2H), 4.37 (dd, J=2.0, 10.0 Hz, 1H), 4.22 (td, J=1.8, 11.0 Hz, 1H), 3.89 (d, J=12.9 Hz, 1H), 3.84 (ddd, J=1.3, 3.4, 11.2 Hz, 1H), 3.70 (dt, J=2.4, 11.4 Hz, 1H), 3.29 (d, J=13.1 Hz, 1H), 2.82 (d, J=4.2 Hz, 1H), 2.60 (d, J=11.2 Hz, 1H), 2.50 (ddd, J=3.9, 10.7, 12.3 Hz, 1H), 2.36 (t, J=10.6 Hz, 1H), 2.33-2.23 (m, 1H), 2.09 (dt, J=3.4, 11.4 Hz, 1H), 1.39 (ddd, J=3.8, 9.1, 12.7 Hz, 1H), 1.28-1.19 (m, 4H), 0.73 (s, 3H).
  • Compound 62: 1H NMR (400 MHz, CD3OD-d4): δ 7.66 (s, 1H), 7.61-7.56 (m, 1H), 7.21-7.16 (m, 2H), 4.44 (d, J=9.6 Hz, 1H), 4.02 (d, J=12.8 Hz, 1H), 3.20-3.12 (m, 3H), 3.04 (d, J=4.0 Hz, 1H), 2.99-2.88 (m, 1H), 2.83-2.76 (m, 1H), 2.42-2.30 (m, 2H), 1.69-1.64 (m, 1H), 1.48 (m, 9H), 1.29 (s, 3H), 1.28-1.17 (m, 1H), 0.88 (s, 3H).
  • Compound 63: 1H NMR (400 MHz, CD3OD-d4): δ 7.65 (s, 1H), 7.60-7.56 (m, 1H), 7.20-7.16 (m, 2H), 4.21 (d, J=12.0 Hz, 1H), 4.04 (d, J=10.4 Hz, 1H), 3.33-3.22 (m, 2H), 3.09-2.86 (m, 4H), 2.39-2.34 (m, 2H), 1.55-1.51 (m, 10H), 1.34-1.29 (m, 4H), 0.83 (s, 3H).
  • Compound 70: 1H NMR (400 MHz, CD3OD-d4): δ 7.61 (s, 1H), 7.60-7.55 (m, 1H), 7.20-7.16 (m, 2H), 4.23 (d, J=10.8 Hz, 1H), 4.02 (d, J=12.8 Hz, 1H), 3.95 (dd, J=11.6, 2.4 Hz, 1H), 3.76-3.70 (m, 1H), 2.99-2.84 (m, 4H), 2.59-2.52 (m, 1H), 2.41-2.35 (m, 1H), 1.40-1.27 (m, 2H), 1.26 (s, 3H), 0.75 (s, 3H).
EXAMPLE 10 IN VITRO RORc LIGAND BINDING ASSAY
This assay was used to determine a compound's potency in inhibiting activity of RORc by determining, Kiapp, IC50, or percent inhibition values. Consumables used in this Example are shown in Table 2 below.
TABLE 2
Consumable Supplier and product code
GFB Unifilter plates Perkin Elmer 6005177
3-[(3- Sigma C5070
Cholamidopropyl)dimethylammonio]-
1-propanesulfonate (CHAPS)
96-well polypropylene U-bottom Nunc 267245
assay plate
HEPES buffer, 1M Sigma H3375
Magnesium chloride (MgCl2) Sigma M8266
D,L-Dithiothreitol (DTT) Sigma D0632
Sodium chloride (NaCl) Sigma 71382
Bovine serum albumin (BSA) Sigma A7030 [lyophilized powder,
≥98% (agarose gel
electrophoresis), Essentially fatty
acid free, essentially globulin free]
25-hydroxycholesterol Sigma H1015
25-[26,27-3H]hydroxycholesterol Perkin Elmer NET674250UC
American Radiolabeled Chemicals
ART0766
RORc ligand binding domain Genentech (e.g., PUR 28048),
expressed in E. coli
Plate seals Perkin Elmer 6005185
Microscint 0 Perkin Elmer 6013611
Table 2

Filter Plate Preparation
On day of the assay, 100 uL of 0.05% CHAPS (in deionized H2O) was added to all wells of the GFB Unifilter plate and allowed soak for 1 h. A wash buffer of 50 mM HEPES (pH 7.4), 150 mM NaCl, and 5 mM MgCl2 was prepared to wash the filter plate. To prepare an assay buffer, BSA was added to the wash buffer to reach 0.01% and DTT was added to reach 1 mM.
Compounds
For IC50 mode, 10 mM compound stocks were serially diluted in DMSO with DMSO to give 20× required final concentration in DMSO (15 uL compound+30 uL DMSO). The 20× compound stocks were diluted in DMSO with Assay Buffer 4-fold to reach 5× the final test concentration in 25% DMSO (10 uL compound+30 uL Assay Buffer). Solutions were mixed by aspiration several times with a pipette set on 50 uL volume. For the assay, 10 uL of 5× compound stock solutions in 25% DMSO were added to the assay plate in duplicate.
For two point screening, 10 mM stock compound solutions were diluted in DMSO to obtain 200 uM (20× the high test concentration) and then diluted 10-fold further to reach 20 uM (20× the low test concentration). The 20× stocks were diluted 4-fold with Assay Buffer (10 uL compound+30 uL Assay Buffer) to reach 5× the test concentrations (50 uM and 5 uM) and 10 uL were added to two assay plates for the duplicate wells. With each concentration tested on 2 plates, each set of 80 compounds used 4 assay plates (1 uM and 10 uM, with n=2).
Nonspecific Binding (NSB) Samples, Total Binding (TB) Samples and No Receptor (No R) Samples
25-hydroxycholesterol (1 uM) was used to determine the level of NSB signal is prepared in DMSO as for compounds above, then diluted in Assay Buffer to give a final concentration of 5 uM. For 25-hydroxycholesterol in 25% DMSO/75% Assay Buffer; 10 uL per well was used for NSB samples. Wells for Total Binding and No Receptor sample determination contained 10 uL of 25% DMSO/75% Assay Buffer per well.
Radioligand (25-[3H]hydroxycholesterol) Preparation
25-[3H]hydroxycholesterol was diluted in Assay Buffer to obtain 15 nM and vortex to mix. Add 20 uL to all wells to reach 6 nM final concentration in the assay.
Receptor Preparation
The optimal concentration for RORc receptor was found to be 0.6 ug/mL. Stock receptor solution was diluted in assay buffer to obtain 1.5 ug/mL in Assay Buffer. 20 uL was added to all wells. For No Receptor samples, 20 uL Assay Buffer was substituted for receptor solution.
Sample Addition to Plates and Incubation
Assay plates were 96-well polypropylene V-bottom plates. 10 uL of 5× compound in 25% DMSO/75% Assay Buffer was added to Test wells. 10 uL of 25% DMSO/75% Assay Buffer was added to Total Binding or No Receptor wells. 10 uL of 5 uM 25-hydroxycholesterol in 25% DMSO/75% Assay Buffer was added to NSB wells. 20 uL of 15 nM 25-[3H]hydroxycholesterol prepared in Assay Buffer was added to all wells. 20 uL of 1.5 ug/mL RORc receptor was added to wells (or 40 uL Assay Buffer to No R wells). Following addition to the wells, the plates were incubated 3 h at 25° C.
Filtration
Using a Packard Filtermate Harvester, the filter plate were washed 4 times following transfer of the incubated samples. Plates were dry-filtered completely (2 h at 50° C. or overnight at room temperature). 50 uL Microscint 0 was added to all wells and read on Topcount protocol Inverted.
Final Concentrations
Final concentrations were as follows: 50 mM HEPES buffer (pH 7.4); 150 mM NaCl; 1 mM DTT; 5 mM MgCl2, 0.01% BSA; 5% DMSO; 0.6 ug/mL RORc receptor; 6 nM 25-[3H]hydroxycholesterol. For NSB wells, 1 uM 25-hydroxycholesterol was also present.
EXAMPLE 11: RORc COACTIVATOR PEPTIDE BINDING ASSAY
Assays were carried out in 16-microL reaction volumes in black 384 Plus F Proxiplates (Perkin-Elmer 6008269). All assay components except test ligand were mixed in coregulator buffer D (Invitrogen PV4420) containing 5 mM DTT and added to the plate at twice their final concentrations in a volume of 8 microL. Test ligands at 2× the final concentration were then added to the wells in 8 □L of coregulator buffer D containing 5 mM DTT and 4% DMSO. Final incubations contained 1× coregulator buffer D, 5 mM DTT, test ligand, 2% DMSO, 50 nM biotinyl-CPSSHSSLTERKHKILHRLLQEGSPS (American Peptide Company; Vista, Calif.), 2 nM Europium anti-GST (Cisbio 61GSTKLB), 12.5 nM streptavidin-D2 (Cisbio 610SADAB), 50 mM KF, and 10 nM of bacterially-expressed human RORc ligand binding domain protein containing an N-terminal 6×His-GST-tag and residues 262-507 of Accession NP_005051. Ten test ligand concentrations were tested in duplicate. After the reaction plates were incubated for 3 h in the dark at room temperature (22-23° C.), the plate was read on an EnVision plate reader (PerkinElmer) following the Europium/D2 HTRF protocol (ex 320, em 615 and 665, 100 □s lag time, 100 flashes, 500 μs window). The time-resolved FRET signal at 665 nm was divided by that at 615 nm to generate the signal ratio of each well. The signal ratio of wells containing RORc and peptide but no test ligand were averaged and set to 0% Effect while the signal ratios of the blank wells containing coactivator peptide but no RORc were averaged and set to −100% Effect. RORc exhibits a basal (constitutive) signal in this assay and test ligands can increase or decrease the signal ratio relative to this basal signal level. RORc agonists increase the signal ratio in this assay and result in a positive % Effect value. Inverse agonists decrease the signal ratio, and result in a negative % Effect value. The EC50 value is the concentration of test compound that provides half-maximal effect (increased or decreased assay signal) and is calculated by Genedata Screener® software (Genedata; Basel, Switzerland) using the following equation:
% Effect=S 0+{(S inf −S 0)/[1+(10logEC 50/10c)n]}
where S0 equals the activity level at zero concentration of test compound, Sinf is the activity level at infinite concentration of test compound, EC50 is the concentration at which the activity reaches 50% of the maximal effect, c is the concentration in logarithmic units corresponding to the values on the x-axis of the dose-response curve plot, and n is the Hill coefficient (the slope of the curve at the EC50)
EXAMPLE 12: ARTHRITIS MOUSE MODEL
8 to 10-week old male DBA/1 (DBA/1OlaHsd, Harlan Laboratories) mice are housed in a specific pathogen free (SPF) animal facility. Arthritis is induced by two injections of collagen subcutaneously in the base of the tail. The initial injection (on day 0) uses bovine type II collagen (2 mg/ml from Chondrex, Redmond, Wash.) emulsified in equal volume of CFA containing 4 mg/ml of M. tuberculosis (Chondrex). The CII booster injection on Day 29 is emulsified in incomplete Freund's adjuvant (IFA). Each animal receives 0.1 ml of emulsion by subcutaneous/intradermal injection in the tail 2 to 3 cm from the body of the mouse. The booster injection site is in the vicinity of but different from the initial injection site and closer to the body of the animal. OR-1050 was formulated in HRC-6 as above. On weekdays, the animals receive two doses (a.m. and p.m.) of HRC-6 or 50 mg/kg OR-1050 p.o. (2.5 mls/kg). On weekends, a single dose of 100 mg/kg is administered (5 mls/kg).
The mice are observed daily for clinical symptoms of CIA based on the following qualitative scale. Each paw was examined individually and scored. Grade 0, normal; grade 1, mild but definite redness and swelling of the ankle or wrist, or apparent redness and swelling limited to individual digits, regardless of the number of affected digits; grade 2, moderate redness and swelling of ankle or wrist; grade 3, severe redness and swelling of the entire paw including digits; grade 4, maximally inflamed limb with involvement of multiple joints. To estimate cumulative disease severity for each animal, an area under the curve score is calculated for each animal by totaling the sum of the daily hind paw measurements betweens days 24 and 48.
EXAMPLE 13: MUSCULAR SCLEROSIS MOUSE MODEL I
Experiments are conducted on female mice aged 4-6 weeks belong to the C57BL/6 strain weighing 17-20 g. Experimental autoimmune encephalomyelitis (EAE) is actively induced using 95% pure synthetic myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) (Invitrogen). Each mouse is anesthetized and receives 200 ug of MOG35-55 peptide and 15 ug of Saponin extract from Quilija bark emulsified in 100 uL of phosphate-buffered saline. A 25 uL volume is injected subcutaneously over four flank areas. Mice are also intraperitoneally injected with 200 ng of pertussis toxin in 200 uL of PBS. A second, identical injection of pertussis toxin is given after 48 h.
A compound of the invention is administered at selected doses. Control animals receive 25 uL of DMSO. Daily treatment extends from day 26 to day 36 post-immunization. Clinical scores are obtained daily from day 0 post-immunization until day 60. Clinical signs are scored using the following protocol: 0, no detectable signs; 0.5, distal tail limpness, hunched appearance and quiet demeanor; 1, completely limp tail; 1.5, limp tail and hindlimb weakness (unsteady gait and poor grip with hind limbs); 2, unilateral partial hind limb paralysis; 2.5, bilateral hind limb paralysis; 3, complete bilateral hindlimb paralysis; 3.5, complete hindlimb paralysis and unilateral forelimb paralysis; 4, total paralysis of hind limbs and forelimbs (Eugster et al., Eur J Immunol 2001, 31, 2302-2312).
Inflammation and demyelination may be assessed by histology on sections from the CNS of EAE mice. Mice are sacrificed after 30 or 60 days and whole spinal cords are removed and placed in 0.32 M sucrose solution at 4° C. overnight. Tissues are prepared and sectioned. Luxol fast blue stain is used to observe areas of demyelination. Haematoxylin and eosin staining is used to highlight areas of inflammation by darkly staining the nuclei of mononuclear cells. Immune cells stained with H&E are counted in a blinded manner under a light microscope. Sections are separated into gray and white matter and each sector is counted manually before being combined to give a total for the section. T cells are immunolabeled with anti-CD3+ monoclonal antibody. After washing, sections are incubated with goat anti-rat HRP secondary antibody. Sections are then washed and counterstained with methyl green. Splenocytes isolated from mice at 30 and 60 days post-immunization are treated with lysis buffer to remove red blood cells. Cells are then re-suspended in PBS and counted. Cells at a density of about 3×106 cells/mL are incubated overnight with 20 ug/mL of MOG peptide. Supernatants from stimulated cells are assayed for IFNgamma protein levels using an appropriate mouse IFN-gamma immunoassay system.
EXAMPLE 14: MUSCULAR SCLEROSIS MOUSE MODEL II
In this model, female rodents are anesthetized with isoflurane and injected with Freund's Incomplete Adjuvant containing 1 mg/mL neuronal antigen (e.g. myelin basic protein, myelin oligodendrocyte glycoprotein, proteolipid protein) and 4 mg/mL mycobacterium tuberculosis at two sites on the back on day 0 of this study. A compound of interest is then dosed daily in a sub-cutaneous, intra-peritoneally, or oral manner from day 0 until the end of study at an efficacious dose. Daily observations of degree of paralysis are taken as measures of efficacy.
EXAMPLE 15: PSORIASIS MOUSE MODEL I
The severe, combined immunodeficient (SCID) mouse model can be used to evaluate the efficacy of compounds for treating psoriasis in humans (Boehncke, Ernst Schering Res Found Workshop 2005, 50, 213-34; and Bhagavathula et al., J Pharmacol Expt'l Therapeutics 2008, 324(3), 938-947). Briefly, SCID mice are used as tissue recipients. One biopsy for each normal or psoriatic volunteer (human) is transplanted onto the dorsal surface of a recipient mouse. Treatment is initiated 1 to 2 weeks after transplantation. Animals with the human skin transplants are divided into treatment groups. Animals are treated twice daily for 14 days. At the end of treatment, animals are photographed and then euthanized. The transplanted human tissue along with the surrounding mouse skin is surgically removed and fixed in 10% formalin and samples obtained for microscopy. Epidermal thickness is measured. Tissue sections are stained with an antibody to the proliferation-associated antigen Ki-67 and with an anti-human CD3.sup.+ monoclonal antibody to detect human T lymphocytes in the transplanted tissue. Sections are also probed with antibodies to c-myc and beta-catenin. A positive response to treatment is reflected by a reduction in the average epiderma thickness of the psoriatic skin transplants. A positive response is also associated with reduced expression of Ki-67 in keratinocytes.
EXAMPLE 16: PSORIASIS MOUSE MODEL II
Using the Imidquimod model of skin inflammation (Fits et al, Journal of Immunology, 2009, 182: 5836-5845), 10-12 week old BALB/c, Il17c+/+ or Il17c−/−, or Il17re+/+ or Il17re−/− mice were administered 50 mg Aldara cream (5% Imidquimod in Graceway, 3M) in the shaved back and right ear daily for 5 days. Clinical scoring and ear thickness measurements were performed daily. Scoring was based upon the manifestation of psoriatic symptoms, such as erythema, scaling and thickness: 0, No disease. 1, Very mild erythema with very mild thickening and scaling involving a small area. 2, Mild erythema with mild thickening and scaling involving a small area. 3, Moderate erythema with moderate thickening and scaling (irregular and patchy) involving a small area (<25%). 4, Severe erythema with marked thickening and scaling (irregular and patchy) involving a moderate area (25-50%). 5, Severe erythema with marked thickening and scaling (irregular and patchy) involving a large area (>50%). Ear and back tissue were harvested on day 5 for histological evaluation. Efficacy of compounds is compared in the imiquimod (IMQ) mouse model of psoriasis. Balb/c mice (10 males/group) received daily topical IMQ (5% cream) on shaved back and right ear for 5 days as described above. Animals received oral dose of a representative compound or DMF (45 or 90 mg-eq MMF/kg twice daily) or vehicle from Day −5 to Day +5. Erythema score is the primary outcome measure.
EXAMPLE 17: IRRITABLE BOWEL DISEASE MOUSE MODEL I
Effectiveness in treatment of inflammatory bowel disease may be evaluated as described by Jurjus et al., J Pharmaocol Toxicol Methods 2004, 50, 81-92; Villegas et al., Int'l Immunopharmacol 2003, 3, 1731-1741; and Murakami et al., Biochemical Pharmacol 2003, 66, 1253-1261. Briefly, female ICR mice are divided into treatment groups which are given either water (control), 5% DSS in tap water is given at the beginning of the experiment to induce colitis, or various concentrations of test compound. After administering test compound for 1 week, 5% DSS in tap water is also administered to the groups receiving test compound for 1 week. At the end of the experiment, all mice are sacrificed and the large intestine is removed. Colonic mucosa samples are obtained and homogenized. Proinflammatory mediators (e.g., IL-1alpha, IL-1beta, TNFalpha, PGE2, and PGF2alpha.) and protein concentrations are quantified. Each excised large intestine is histologically examined and the damage to the colon scored.
EXAMPLE 18: CHRONIC OBSTRUCTIVE PULMONARY DISEASE MOUSE MODEL
The cigarette smoke model of Martorana et al., Am J Respir Crit Care Med 2005, 172, 848-835; and Cavarra et al., Am J Respir Crit Care Med 2001, 164, 886-890 can be used for assessing efficacy in treating emphysema. Briefly, six-week old C57B1/6J male mice are exposed either to room air or to the smoke of five cigarettes for 20 minutes. For the acute study, mice are divided into three groups of 40 animals each. These groups are then divided into four subgroups of 10 mice each as follows: (1) no treatment/air-exposed; (2) no treatment/smoke-exposed; (3) a first dose of test compound plus smoke-exposed; and (4) a second dose of test compound. In the first group, trolox equivalent antioxidant capacity is assessed at the end of the exposure in bronchoalveolar lavage fluid. In the second group, cytokines and chemokines are determined in bronchoalveolar lavage fluid using a commercial cytokine panel at 4 hours; and in the third group bronchoalveolar lavage fluid cell count is assessed at 24 hours.
In a chronic study, the mice are exposed to either room air or to the smoke of three cigarettes/day, for 5 days/week, for 7 months. Five groups of animals are used: (1) no treatment/air-exposed; (2) a first dose of a test compound plus air-exposed; (3) no treatment/smoke-exposed; (4) a second dose of the test compound plus smoke-exposed; and (5) the first dose of the test compound plus smoke exposed. Seven months after chronic exposure to room air or cigarette smoke, 5 to 12 animals from each group are sacrificed and the lungs fixed intratracheally with formalin. Lung volume is measured by water displacement. Lungs are stained. Assessment of emphysema includes mean linear intercept and internal surface area. The volume density of macrophages, marked immunohistochemically with anti-mouse Mac-3 monoclonal antibodies is determined by point counting. A mouse is considered to have goblet cell metaplasia when at least one or more midsize bronchi/lung showed a positive periodic acid-Schiff staining for the determination of desmosine, fresh lungs are homogenized, processed, and analyzed by high-pressure liquid chromatography.
EXAMPLE 19: ASTHMA MOUSE MODEL
A single inhaled allergen challenge can induce an acute increase in airway responsiveness in some individuals and animal models. However, repeated allergen inhalations have demonstrated more pronounced, consistent, and prolonged increases in airway responsiveness. This mouse model of long-term repeated inhalations of allergen has been used to study the long term effect of allergic diseases in the lung, and to delineate the cells, mechanisms, molecules, and mediators involved in the induction of airway hyperresponsiveness of lung in humans.
Crystalline OVA is obtained from Pierce Chem. Co. (Rockford, Ill.) aluminum potassium sulfate (alum) from Sigma Chem. Co. (St. Louis, Mo.), pyrogen-free distilled water from Baxter, Healthcare Corporation (Deerfield, Ill.), 0.9% sodium chloride (normal saline) from Lymphomed (Deerfield, Ill.) and Trappsol™. HPB-L100 (aqueous hydroxypropylbeta cyclodextrin; 45 wt/vol % aqueous solution) from Cyclodextrin Technologies Development, Inc. (Gainesville, Fla.). The OVA (500 ug/ml in normal saline) is mixed with equal volumes of 10% (wt/vol) alum in distilled water. The mixture (pH 6.5 using 10 N NaOH) after incubation for 60 minutes at room temperature is centrifuged at 750 g for 5 minutes; the pellet resuspended to the original volume in distilled water and used within one hour. The selective 5-lipoxtgenase inhibitor, Zileuton (N[1-benzo[b]thien-2-ylethyl]-N-hydroxyurea; J. Pharmacol Exp Ther. 1991; 256: 929-937) is dissolved in Trappsol.™. Histatek, Inc. (Seattle, Wash.) to provide the mast cell degranulation inhibitor, f-Met-Leu-Phe-Phe (“HK-X”).
Female BALB/c Once (6-8 wk of age) receive an i.p. injection of 0.2 ml (100 ug) of OVA with alum (J. Exp Med. 1996; 184: 1483-1494). Mice are anesthetized with 0.2 ml i.p. of ketamine (0.44 mg/ml)/xylazine (6.3 mg/ml) in normal saline before receiving an intranasal (i.n.) dose of 100 ug OVA in 0.05 ml normal saline and an i.n. dose of 50 ug OVA in 0.05 ml normal saline separately on different days. Two control groups are used: the first group receives normal saline with alum i.p. and normal saline without alum i.n.; and the second group receives OVA with alum i.p., OVA without alum i.n., and normal saline, alone.
The trachea and left lung (the right lung may be used for bronchoalveolar lavage (“BAL”) as described below) are obtained and fixed in 10% neutral formaldehyde solution at room temperature for about 15 h. After being embedded in paraffin, the tissues are cut into 5-um sections and processed with the different staining or immunolabling further. Discombe's eosinophil staining is used for counting the cell numbers with the counterstain of methylene blue. The eosinophil number per unit airway area (2,200 um2) is determined by morphometry (J. Pathol. 1992; 166: 395-404; Am Rev Respir Dis. 1993; 147:448-456). Fibrosis is identified with the Masson's trichrome staining. Airway mucus iss identified by the following staining method: methylene blue, hematoxylin and eosin, mucicarmine, alcian blue, and alcian blue/periodic acid-Schiff (PAS) reaction (Troyer, H., “Carbohydrates” in Principles and Techniques of Histochemistry, Little, Brown and Company, Boston, Mass., 1980: 89-121; Sheehan, D. C., et al., “Carbohydrates” in Theory and Practice of Histotechnology, Battle Press, Columbus, Ohio, 1980: 159-179) Mucin is stained with mucicarmine solution; metanil yellow counterstain is employed. Acidic mucin and sulfated mucosubstances are stained with alcian blue, pH 2.5; nuclear fast red counterstain is used. Neutral and acidic mucosubstances are identified by alcian blue, pH 2.5, and PAS reaction. The degree of mucus plugging of the airways (0.5-0.8 mm in diameter) is also assessed by morphometry. The percent occlusion of airway diameter by mucus iss classified on a semiquantitative scale from 0 to 4+. The histologic and morphometric analyses may be performed by individuals blinded to the protocol design.
On day 28, 24 hours after the last i.n. administration of either normal saline or OVA, pulmonary mechanics to intravenous infusion of methacholine may be determined in mice in vivo by a plethysmographic method as previously described (10, 1958; 192: 364-368; J. Appl. Physiol. 1988; 64: 2318-2323; J. Exp. Med. 1996; 184: 1483-1494).
After tying off the left lung at the mainstem bronchus, the right lung may be lavaged three times with 0.4 ml of normal saline. Bronchoalveolar lavage (BAL) fluid cells from a 0.05-ml aliquot of the pooled sample are counted using a hemocytometer and the remaining fluid centrifuged at 4° C. for 10 minutes at 200 g. The supernatant may be stored at 70.degree. C. until eicosanoid analysis is performed. After resuspension of the cell pellet in normal saline containing 10% bovine serum albumin (“BSA”), BAL cell smears are made on glass slides. To stain eosinophils, dried slides are stained with Discombe's diluting fluid (0.05% aqueous eosin and 5% acetone (vol/vol) in distilled water; J. Exp. Med. 1970; 131: 1271-1287) for 5-8 minutes, rinsed with water for 0.5 minutes, and counterstained with 0.07% methylene blue for 2 minutes.
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims (13)

What is claimed is:
1. A compound of formula I
Figure US09994551-20180612-C00216
or a pharmaceutically acceptable salt thereof, wherein:
R1 is:
halo;
R2 is:
hydrogen; or
halo;
R3 is:
hydrogen;
C1-6alkyl; or
halo;
R4 is:
C1-6alkyl;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
halo-C1-6alkylsulfonyl;
aminocarbonyl-C1-6alkyl;
N-C1-6alkyl-aminocarbonyl-C1-6alkyl;
N,N-C1-6dialkyl-aminocarbonyl-C1-6alkyl;
hydroxycarbonyl-C1-6alkyl;
C1-6alkoxycarbonyl-C1-6alkyl;
C1-6alkylcarbonylamino;
—C1-6alkylene-C(O)—NRaRb wherein the C1-6alkylene- may be substituted once or twice with Rc;
C3-6cycloalkyl which may be unsubstituted or substituted once or twice with Rd;
hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with Re; or
heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Re;
Ra is:
hydrogen; or
C1-6alkyl;
Rb is:
hydrogen;
C1-6alkyl;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
C1-6alkoxy-C1-6alkyl;
C1-6alkylsulfonyl-C1-6alkyl;
C3-6cycloalkyl;
C3-6cycloalkyl-C1-6alkyl;
aminocarbonyl-C1-6alkyl;
heterocyclyl selected from: oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with Rf;
heterocyclyl-C1-6alkyl wherein the heterocycly is selected from oxetanyl and azetidinyl, each of which may be unsubstituted or substituted once or twice with Rf;
hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; or tetrazolyl; each of which may be unsubstituted or substituted once or twice with Rg; or
heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; or tetrazolyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Rg;
or Ra and Rb together with the nitrogen atom to which they are attached may form a heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl or oxazepinyl, each may be unsubstituted or substituted once or twice with Rf;
Rc is:
halo;
hydroxyl; or
C3-6cycloalkyl;
Rd is:
C1-6alkyl;
halo;
hydroxyl; or
oxo;
Re is:
C1-6alkyl;
halo;
hydroxyl;
oxo;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
C1-6alkoxy-C1-6alkyl;
C1-6alkylsulfonyl-C1-6alkyl;
C3-6cycloalkyl;
C3-6cycloalkyl-C1-6alkyl;
aminocarbonyl-C1-6alkyl; or
—C(O)NHRh;
Rf is:
C1-6alkyl;
halo;
hydroxyl;
cyano;
oxo;
C1-6alkylsulfonyl;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
C1-6alkoxy-C1-6alkyl; or
C1-6alkylsulfonyl-C1-6alkyl;
Rg is:
C1-6alkyl;
hydroxyl;
hydroxy-C1-6alkyl; or
oxo;
Rh is:
C1-6alkyl;
hydroxy-C1-6alkyl; or
halo-C1-6alkyl.
2. The compound of claim 1, wherein R1 and R2 are halo.
3. The compound of claim 1, wherein R1 and R2 are fluoro.
4. The compound of claim 1, wherein R3 is hydrogen..
5. The compound of claim 1, wherein R4 is —C1-6alkylene-C(O)-NRaRb wherein the C1-6alkylene- may be substituted once or twice with Rc.
6. The compound of claim 1, wherein R4 is hetereoaryl selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl, each of which may be unsubstituted or substituted once or twice with Re.
7. The compound of claim 1, wherein R4 is heteroaryl-C1-6alkyl wherein the heteroaryl is selected from oxazolyl; isoxazolyl; oxadiazolyl; thiazolyl; isothiazolyl; thiadiazolyl; triazolyl; pyrrolyl; pyrazolyl; imidazolyl; tetrazolyl; pyridinyl; pyrimidinyl; pyrazinyl; and pyridazinyl; wherein the heteroaryl portion of each may be unsubstituted or substituted once or twice with Re.
8. A compound of formula II
Figure US09994551-20180612-C00217
or pharmaceutically acceptable salts thereof, wherein:
m is: 0; or 1;
n is: 0; or 1;
p is: 0; 1; or 2;
q is: 0; or 1;
X is: C; O; or N;
Y is: C; O; or N;
R1 is:
halo;
R2 is:
hydrogen; or
halo;
R3 is:
hydrogen;
C1-6alkyl; or
halo;
R5 is:
C1-6alkyl; or
oxo;
R6 is:
C1-6alkyl;
halo-C1-6alkyl;
hydroxy-C1-6alkyl;
benzyl;
C1-6alkoxycarbonyl;
C1-6alkylcarbonyl;
C1-6alkylsulfonyl;
aminocarbonyl;
—C(O)—NRjRk;
aminosulfonyl;
hydroxy-C1-6alkylcarbonyl;
heteroaryl selected from: pyridinyl; pyrimidinyl; pyridazinyl; pyrazinyl; oxadiazolyl; oxazoyl; oxazolidinyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with Ri;
heteroarylcarbonyl wherein the heteroaryl portion is selected from: pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; oxadiazolyl; oxazoyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with Ri;
heteroaryl-C1-6alkyl wherein the heteroaryl portion is selected from: pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; oxadiazolyl; oxazoyl; isoxazolyl; and triazolyl; each of which may be unsubstituted or substituted once or twice with Ri;
Ri is:
C1-6alkyl;
halo-C1-6alkyl;
C1-6alkoxycarbonyl;
benzyl;
halo;
hydroxyl;
hydroxy-C1-6alkyl; or
oxo;
Rj is:
hydrogen; or
C1-6alkyl; and
Rk is:
hydrogen;
C1-6alkyl;
hydroxy-C1-6alkyl;
C3-6cycloalkyl which may be unsubstituted or substituted once or twice with Ri;
C3-6cycloalkyl-C1-6alkyl wherein the C3-6cycloalkyl portion may be unsubstituted or substituted once or twice with Ri
heterocyclyl selected from oxetanyl and azetedinyl which may be unsubstituted or substituted once or twice with Ri; or
heterocyclyl-C1-6alkyl wherein the heterocyclyl portion is selected from oxetanyl and azetedinyl and may be unsubstituted or substituted once or twice with Ri.
9. The compound of claim 8, wherein said compound is of formula III
Figure US09994551-20180612-C00218
10. The compound of claim 8, wherein said compound is of formula IV
Figure US09994551-20180612-C00219
11. The compound of claim 8, wherein said compound is of formula V
Figure US09994551-20180612-C00220
12. A composition comprising:
(a) a pharmaceutically acceptable carrier; and
(b) a compound of claim 1.
13. A method for treating a disease selected from rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, juvenile arthritis, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), psoriasis, biliary colic, renal colic, diarrhea-dominant IBS, muscular sclerosis, Sjogren's disease, lupus, and pulmonary fibrosis, the method comprising administering to a subject in need thereof an effective amount of a compound of claim 1.
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